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1
Merski, Matthew, Marcus Fischer, Trent E. Balius, Oliv Eidam, and Brian K. Shoichet. "Homologous ligands accommodated by discrete conformations of a buried cavity." Proceedings of the National Academy of Sciences 112, no. 16 (April 6, 2015): 5039–44. http://dx.doi.org/10.1073/pnas.1500806112.
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Conformational change in protein–ligand complexes is widely modeled, but the protein accommodation expected on binding a congeneric series of ligands has received less attention. Given their use in medicinal chemistry, there are surprisingly few substantial series of congeneric ligand complexes in the Protein Data Bank (PDB). Here we determine the structures of eight alkyl benzenes, in single-methylene increases from benzene to n-hexylbenzene, bound to an enclosed cavity in T4 lysozyme. The volume of the apo cavity suffices to accommodate benzene but, even with toluene, larger cavity conformations become observable in the electron density, and over the series two other major conformations are observed. These involve discrete changes in main-chain conformation, expanding the site; few continuous changes in the site are observed. In most structures, two discrete protein conformations are observed simultaneously, and energetic considerations suggest that these conformations are low in energy relative to the ground state. An analysis of 121 lysozyme cavity structures in the PDB finds that these three conformations dominate the previously determined structures, largely modeled in a single conformation. An investigation of the few congeneric series in the PDB suggests that discrete changes are common adaptations to a series of growing ligands. The discrete, but relatively few, conformational states observed here, and their energetic accessibility, may have implications for anticipating protein conformational change in ligand design.
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Shang, Jinsai, Richard Brust, Patrick R. Griffin, Theodore M. Kamenecka, and Douglas J. Kojetin. "Quantitative structural assessment of graded receptor agonism." Proceedings of the National Academy of Sciences 116, no. 44 (October 14, 2019): 22179–88. http://dx.doi.org/10.1073/pnas.1909016116.
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Ligand–receptor interactions, which are ubiquitous in physiology, are described by theoretical models of receptor pharmacology. Structural evidence for graded efficacy receptor conformations predicted by receptor theory has been limited but is critical to fully validate theoretical models. We applied quantitative structure–function approaches to characterize the effects of structurally similar and structurally diverse agonists on the conformational ensemble of nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ). For all ligands, agonist functional efficacy is correlated to a shift in the conformational ensemble equilibrium from a ground state toward an active state, which is detected by NMR spectroscopy but not observed in crystal structures. For the structurally similar ligands, ligand potency and affinity are also correlated to efficacy and conformation, indicating ligand residence times among related analogs may influence receptor conformation and function. Our results derived from quantitative graded activity–conformation correlations provide experimental evidence and a platform with which to extend and test theoretical models of receptor pharmacology to more accurately describe and predict ligand-dependent receptor activity.
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LEE, HO-JIN, HYUN-MEE PARK, and KANG-BONG LEE. "CONFORMATIONAL PREFERENCES OF N-ACETYL–GLYCINE–GLYCINE–N′-METHYLAMIDE: A THEORETICAL STUDY." Journal of Theoretical and Computational Chemistry 08, no. 05 (October 2009): 799–811. http://dx.doi.org/10.1142/s0219633609005118.
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The conformational preferences of peptide models have been investigated to understand the protein folding mechanism and to develop the force field. Here, we report the minimum energy conformations for a model peptide, N-acetyl–glycine–glycine–N′-methylamide ( Ac–1Gly–2Gly–NHMe(I) ) at the HF/3-21G, HF/6-31G*, and the B3LYP/6-31G* level of theory. At the B3LYP/6-31G* level, the 31 minima were identified and the 10 β-turn structures among the minima were observed in gas-phase. The conformational preferences of Gly residue in the model peptide, I depend on its relative position and conformation of neighboring Gly residue. The Gly residue in this model dipeptide has an asymmetric energy profile as one of Gly residue adopts a specific conformation. This study sheds some lights on understanding the unique conformational preferences of Gly residue in protein including two consecutive Gly residues.
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Whitmore, Elizabeth K., Devon Martin, and Olgun Guvench. "Constructing 3-Dimensional Atomic-Resolution Models of Nonsulfated Glycosaminoglycans with Arbitrary Lengths Using Conformations from Molecular Dynamics." International Journal of Molecular Sciences 21, no. 20 (October 18, 2020): 7699. http://dx.doi.org/10.3390/ijms21207699.
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Glycosaminoglycans (GAGs) are the linear carbohydrate components of proteoglycans (PGs) and are key mediators in the bioactivity of PGs in animal tissue. GAGs are heterogeneous, conformationally complex, and polydisperse, containing up to 200 monosaccharide units. These complexities make studying GAG conformation a challenge for existing experimental and computational methods. We previously described an algorithm we developed that applies conformational parameters (i.e., all bond lengths, bond angles, and dihedral angles) from molecular dynamics (MD) simulations of nonsulfated chondroitin GAG 20-mers to construct 3-D atomic-resolution models of nonsulfated chondroitin GAGs of arbitrary length. In the current study, we applied our algorithm to other GAGs, including hyaluronan and nonsulfated forms of dermatan, keratan, and heparan and expanded our database of MD-generated GAG conformations. Here, we show that individual glycosidic linkages and monosaccharide rings in 10- and 20-mers of hyaluronan and nonsulfated dermatan, keratan, and heparan behave randomly and independently in MD simulation and, therefore, using a database of MD-generated 20-mer conformations, that our algorithm can construct conformational ensembles of 10- and 20-mers of various GAG types that accurately represent the backbone flexibility seen in MD simulations. Furthermore, our algorithm efficiently constructs conformational ensembles of GAG 200-mers that we would reasonably expect from MD simulations.
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Giri Rao, V. V. Hemanth, and Shachi Gosavi. "On the folding of a structurally complex protein to its metastable active state." Proceedings of the National Academy of Sciences 115, no. 9 (January 17, 2018): 1998–2003. http://dx.doi.org/10.1073/pnas.1708173115.
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For successful protease inhibition, the reactive center loop (RCL) of the two-domain serine protease inhibitor, α1-antitrypsin (α1-AT), needs to remain exposed in a metastable active conformation. The α1-AT RCL is sequestered in a β-sheet in the stable latent conformation. Thus, to be functional, α1-AT must always fold to a metastable conformation while avoiding folding to a stable conformation. We explore the structural basis of this choice using folding simulations of coarse-grained structure-based models of the two α1-AT conformations. Our simulations capture the key features of folding experiments performed on both conformations. The simulations also show that the free energy barrier to fold to the latent conformation is much larger than the barrier to fold to the active conformation. An entropically stabilized on-pathway intermediate lowers the barrier for folding to the active conformation. In this intermediate, the RCL is in an exposed configuration, and only one of the two α1-AT domains is folded. In contrast, early conversion of the RCL into a β-strand increases the coupling between the two α1-AT domains in the transition state and creates a larger barrier for folding to the latent conformation. Thus, unlike what happens in several proteins, where separate regions promote folding and function, the structure of the RCL, formed early during folding, determines both the conformational and the functional fate of α1-AT. Further, the short 12-residue RCL modulates the free energy barrier and the folding cooperativity of the large 370-residue α1-AT. Finally, we suggest experiments to test the predicted folding mechanism for the latent state.
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Ludwiczak, Jan, Ewa Szczęsna, Antônio Marinho da Silva Neto, Piotr Cieplak, Andrzej A. Kasprzak, and Adam Jarmuła. "Interactions between motor domains in kinesin-14 Ncd — a molecular dynamics study." Biochemical Journal 476, no. 17 (September 10, 2019): 2449–62. http://dx.doi.org/10.1042/bcj20190484.
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Abstract Minus-end directed, non-processive kinesin-14 Ncd is a dimeric protein with C-terminally located motor domains (heads). Generation of the power-stroke by Ncd consists of a lever-like rotation of a long superhelical ‘stalk’ segment while one of the kinesin's heads is bound to the microtubule. The last ∼30 amino acids of Ncd head play a crucial but still poorly understood role in this process. Here, we used accelerated molecular dynamics simulations to explore the conformational dynamics of several systems built upon two crystal structures of Ncd, the asymmetrical T436S mutant in pre-stroke/post-stroke conformations of two partner subunits and the symmetrical wild-type protein in pre-stroke conformation of both subunits. The results revealed a new conformational state forming following the inward motion of the subunits and stabilized with several hydrogen bonds to residues located on the border or within the C-terminal linker, i.e. a modeled extension of the C-terminus by residues 675–683. Forming of this new, compact Ncd conformation critically depends on the length of the C-terminus extending to at least residue 681. Moreover, the associative motion leading to the compact conformation is accompanied by a partial lateral rotation of the stalk. We propose that the stable compact conformation of Ncd may represent an initial state of the working stroke.
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Lane, A. N., T. C. Jenkins, D. J. Brown, and T. Brown. "N.m.r. determination of the solution conformation and dynamics of the A.G mismatch in the d(CGCAAATTGGCG)2 dodecamer." Biochemical Journal 279, no. 1 (October 1, 1991): 269–81. http://dx.doi.org/10.1042/bj2790269.
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A.G base-paired mismatches that occur during replication are among the most difficult to detect by repair enzymes. Such purine.purine mispairs can exist in two conformations, one of which is stabilized by protons [Gao & Patel (1988) J. Am. Chem. Soc. 110, 5178-5182]. We have undertaken a 1H-n.m.r. and 31P-n.m.r. study of the mismatched dodecamer d(CGCAAATTGGCG)2 as a function of both temperature and pH to determine the conformational features of the A.G mismatch. At pH greater than 7 the mispaired bases are each in the anti conformation and are stacked in the B-like helix. As the pH is decreased, a second conformation becomes populated (apparent pKa approx. 5.9) with concomitant changes in the chemical shifts of protons of the mispaired bases and their nearest neighbours. Data from two-dimensional nuclear-Overhauser-enhancement spectroscopy show unequivocally that, at low pH, the dominant conformation is one in which the mismatched G residues are in the syn conformation and are hydrogen-bonded to the A residues that remain in the anti conformation. Residues not adjacent to the A.G sites are almost unaffected by the transition or the mispairing, suggesting considerable local flexibility of the unconstrained duplexes. Despite the bulging of the mispaired bases, the conformation of the A(anti).G(anti) duplex is very similar to the native dodecamer, whereas the AH+(anti).G(syn) duplex shows a greater variation in the backbone conformation at the mismatched site. According to the chemical shifts, the duplex retains twofold symmetry in solution. The equilibrium between the syn and anti conformations of G9/G21 is strongly dependent on pH, but only weakly dependent on temperature (delta H approx. 16 kJ.mol-1). The first-order rate constant for the transition is approx. 9 s-1 at 283 K and approx. 60 s-1 at 298 K, with an activation enthalpy of approx. 100 kJ.mol-1. The stabilization of the A(anti).G(syn) conformation by protons is consistent with models invoking N1 protonation of adenine. Using the derived glycosidic torsion angles we have used restrained molecular dynamics to build models of the neutral and protonated d(CGCAAATTGGCG)2 oligomers. The results confirm that the A(anti).G(anti) and AH+(anti).G(syn) conformations are favoured at high pH and low pH respectively, in accord with n.m.r. and single-crystal X-ray data.
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Kumar, Sivakumar Prasanth, and Prakash Chandra Jha. "Multi-Pharmacophore Modeling of Caspase-3 Inhibitors using Crystal, Dock and Flexible Conformation Schemes." Combinatorial Chemistry & High Throughput Screening 21, no. 1 (March 20, 2018): 26–40. http://dx.doi.org/10.2174/1386207321666180102114917.
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Aim and Objective: Numerous caspase-3 drug discovery projects were found to have relied on single receptor as the template to recognize most promising small molecule candidates using docking approach. Alternatively, some researchers were contingent upon ligand-based alignment to build up an empirical relationship between ligand functional groups and caspase-3 inhibitory activity quantitatively. To connect both caspase-3 receptor details and its inhibitors chemical functionalities, this study was undertaken to develop receptor- and ligand-pharmacophore models based on different conformational schemes. Material and Methods: A multi-pharmacophore modeling strategy is carried out based on three conformational schemes of pharmacophore hypothesis generation to screen caspase-3 inhibitors from database. The schemes include (i) flexible (conformations unrestricted or flexible during pharmacophore mapping), (ii) dock (conformations obtained using FlexX docking method) and (iii) crystal (extracted from multiple caspase-3-ligand complexes from PDB repository) conformations of query ligands. The pharmacophore models developed using these conformational schemes were then used to identify probable caspase-3 inhibitors from ZINC database. Results: We noticed better sensitivity with good specificity measures returned by candidate pharmacophore hypotheses across each conformation type and recognized crucial pharmacophore features that enable caspase-3 binding. Pharmacophore modeling based on flexible conformational scheme indicated that the crystal structure 3KJF (AAAADH) is the best receptor structure to perform receptor-based pharmacophore screening of caspase-3 inhibitors. When multiple crystal structures were included, the hypothesis (HAAA) is more generalized. Superimposition of multiple co-crystal ligands from various caspase-3 PDB entries in crystallographic binding mode revealed similar hypothesis (HAAA). Further, FlexX-guided dock conformations of validation dataset showed that the crystal structure 1RE1 is the best-suited for dock-based pharmacophore models. Database screening using these pharmacophore hypotheses identified N'-[6-(benzimidazol-1-yl)-5-nitro-pyrimidin-4-yl]-4 methylbenzenesulfonohydrazide and 2-nitro-N'-[5-nitro-6-[N'-(p-tolylsulfonyl)hydrazino]pyrimidin-4- yl]benzohydrazide as the probable caspase-3 inhibitors. Conclusion: N'-[6-(benzimidazol-1-yl)-5-nitro-pyrimidin-4-yl]-4 methylbenzenesulfonohydrazide and 2-nitro-N'-[5-nitro-6-[N'-(p-tolylsulfonyl)hydrazino]pyrimidin-4-yl]benzohydrazide may be tested for caspase-3 inhibition. We believe that potential caspase-3 inhibitors can be recognized efficiently by adapting multi-pharmacophore models in database screening.
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Li, Haiyan, Zanxia Cao, Guodong Hu, Liling Zhao, Chunling Wang, and Jihua Wang. "Ligand-induced structural changes analysis of ribose-binding protein as studied by molecular dynamics simulations." Technology and Health Care 29 (March 25, 2021): 103–14. http://dx.doi.org/10.3233/thc-218011.
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BACKGROUND: The ribose-binding protein (RBP) from Escherichia coli is one of the representative structures of periplasmic binding proteins. Binding of ribose at the cleft between two domains causes a conformational change corresponding to a closure of two domains around the ligand. The RBP has been crystallized in the open and closed conformations. OBJECTIVE: With the complex trajectory as a control, our goal was to study the conformation changes induced by the detachment of the ligand, and the results have been revealed from two computational tools, MD simulations and elastic network models. METHODS: Molecular dynamics (MD) simulations were performed to study the conformation changes of RBP starting from the open-apo, closed-holo and closed-apo conformations. RESULTS: The evolution of the domain opening angle θ clearly indicates large structural changes. The simulations indicate that the closed states in the absence of ribose are inclined to transition to the open states and that ribose-free RBP exists in a wide range of conformations. The first three dominant principal motions derived from the closed-apo trajectories, consisting of rotating, bending and twisting motions, account for the major rearrangement of the domains from the closed to the open conformation. CONCLUSIONS: The motions showed a strong one-to-one correspondence with the slowest modes from our previous study of RBP with the anisotropic network model (ANM). The results obtained for RBP contribute to the generalization of robustness for protein domain motion studies using either the ANM or PCA for trajectories obtained from MD.
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Freitas, Matheus Puggina de, and Teodorico de Castro Ramalho. "Employing conformational analysis in the molecular modeling of agrochemicals: insights on QSAR parameters of 2,4-D." Ciência e Agrotecnologia 37, no. 6 (December 2013): 485–94. http://dx.doi.org/10.1590/s1413-70542013000600001.
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A common practice to compute ligand conformations of compounds with various degrees of freedom to be used in molecular modeling (QSAR and docking studies) is to perform a conformational distribution based on repeated random sampling, such as Monte-Carlo methods. Further calculations are often required. This short review describes some methods used for conformational analysis and the implications of using selected conformations in QSAR. A case study is developed for 2,4-dichlorophenoxyacetic acid (2,4-D), a widely used herbicide which binds to TIR1 ubiquitin ligase enzyme. The use of such an approach and semi-empirical calculations did not achieve all possible minima for 2,4-D. In addition, the conformations and respective energies obtained by the semi-empirical AM1 method do not match the calculated trends obtained by a high level DFT method. Similar findings were obtained for the carboxylate anion, which is the bioactive form. Finally, the crystal bioactive structure of 2,4-D was not found as a minimum when using Monte-Carlo/AM1 and is similarly populated with another conformer in implicit water solution according to optimization at the B3LYP/aug-cc-pVDZ level. Therefore, quantitative structure-activity relationship (QSAR) methods based on three dimensional chemical structures are not fundamental to provide predictive models for 2,4-D congeners as TIR1 ubiquitin ligase ligands, since they do not necessarily reflect the bioactive conformation of this molecule. This probably extends to other systems.
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Wolfe, Saul, Kiyull Yang, and Maged Khalil. "Conformation–activity relationships and the mechanism of action of penicillin." Canadian Journal of Chemistry 66, no. 11 (November 1, 1988): 2733–50. http://dx.doi.org/10.1139/v88-424.
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Using the MMPEN parameters of Allinger's MMP2(85) force field, a conformational analysis has been performed on four biologically active penicillins; D-ampicillin, L-α-phenoxyethylpenicillin, penicillin G, and penicillin V, and on five biologically inactive or much less active penicillins: L-ampicillin, D-α-phenoxyethylpenicillin, N-methylpenicillin G, 6α-methylpenicillin G, and bisnorpenicillin G. Antibacterial activity is found to be associated with the existence of a global minimum having a compact structure, whose convex face is accessible to a penicillin binding protein (PBP), with the C3-carboxyl group and the side-chain N-H exposed on this face. Using the MMPEP parameters of MMP2(85), a conformational analysis has been performed on phenylacetyl-D-Ala-D-Ala-O−, a peptide model of the normal substrate of a PBP. Labischinski's global minimum has been reproduced, along with structures that correspond to Tipper and Strominger's proposal that the N4—C7 bond of a penicillin corresponds to the Ala–Ala peptide bond, and to Hasan's proposal that the N4—C5 bond of penicillin corresponds to the peptide bond. For both models, conformations of the peptide related to the pseudoaxial and pseudoequatorial conformations of the thiazolidine ring of penicillin G have been examined. It is concluded that penicillin is not a structural analog of the global minimum of the peptide; however, comparisons based on unbound conformations of PBP substrates are unable to determine which model is more appropriate, or which conformation of penicillin G is the biologically significant one. Using the ECEPP/MMPEP strategy, a model of the active site of a PBP has been obtained, following a search of 200,000 structures of the peptide Ac-NH-Val-Gly-Ser-Val-Thr-Lys-NH-Me. This peptide contains the sequence at the active site of a PBP of Streptomyces R61, for which it is also known that the C3-carboxyl group of penicillin binds to the ε-amino group of lysine, and the β-lactam reacts chemically with the serine OH. The lysine and serine side chains and the C-terminal carbonyl group are found to occupy the concave face of the active site model.A strategy for the docking of penicillins or peptides to this model, with full minimization of the conformational energies of the complexes, has been devised. All active penicillins bind through strong hydrogen bonds to the C3-carboxyl group and the side-chain N-H, and with a four-centered relationship between the O-H of serine and the (O)C-N of the β-lactam ring. The geometrical parameters of this relationship are reminiscent of those found in the gas phase transition state of neutral hydration of a carbonyl group. When the energies of formation and geometries of the pseudoaxial and pseudoequatorial penicillin G complexes are examined, there is now a clear preference for the binding of the pseudoaxial conformation, which is the global minimum of the uncomplexed penicillin in this case. A similar examination of the peptide complexes reveals that only the conformation of the peptide that corresponds to Tipper and Strominger's model, and is based on the pseudoaxial conformation of penicillin G, can form a complex with a geometry and energy comparable to those of a biologically active penicillin.
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Rho, Yecheol, Jun Ha Kim, Byoungseok Min, and Kyeong Sik Jin. "Chemically Denatured Structures of Porcine Pepsin using Small-Angle X-ray Scattering." Polymers 11, no. 12 (December 14, 2019): 2104. http://dx.doi.org/10.3390/polym11122104.
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Porcine pepsin is a gastric aspartic proteinase that reportedly plays a pivotal role in the digestive process of many vertebrates. We have investigated the three-dimensional (3D) structure and conformational transition of porcine pepsin in solution over a wide range of denaturant urea concentrations (0–10 M) using Raman spectroscopy and small-angle X-ray scattering. Furthermore, 3D GASBOR ab initio structural models, which provide an adequate conformational description of pepsin under varying denatured conditions, were successfully constructed. It was shown that pepsin molecules retain native conformation at 0–5 M urea, undergo partial denaturation at 6 M urea, and display a strongly unfolded conformation at 7–10 M urea. According to the resulting GASBOR solution models, we identified an intermediate pepsin conformation that was dominant during the early stage of denaturation. We believe that the structural evidence presented here provides useful insights into the relationship between enzymatic activity and conformation of porcine pepsin at different states of denaturation.
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Jia, Zhe, Lin Li, Yunhui Peng, Feng Ding, and Emil Alexov. "The capricious electrostatic force: Revealing the signaling pathway in integrin α2-I domain." Journal of Theoretical and Computational Chemistry 17, no. 03 (May 2018): 1840001. http://dx.doi.org/10.1142/s0219633618400011.
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Integrins are cellular adhesion proteins located on cell surface. They are known to have open and closed conformations that correspond to high and low binding affinity to ligands, respectively. Integrin [Formula: see text]2 binds to the ligands via the ligand binding domain, [Formula: see text]2-I domain, which also has open and closed conformations. Experimentally, the closed to open conformation change is shown to be triggered by pulling the C-terminal away from the ligand binding site, but how the signal propagates from the distant C-terminal to the binding site is unknown. To explain the mechanisms of the conformation change, we built models of the [Formula: see text]2-I domain open and closed conformations in ligand free and ligand bound states, respectively. We found that the signaling pathway consists of F313-I280-V252 residues that connect the C-terminal and the ligand binding site. The pathway is highly conserved as revealed by a protein sequence analysis among 55 species. Furthermore, MM/PBSA energy calculations on the stabilities and ligand binding affinities of the closed and open conformations are consistent with experimental measurements. The open conformation is more favorable for ligand binding, and the closed conformation is more stable in unbound state. Energy analysis also revealed the “hot spots” for ligand binding, and most residues that contribute strongly to ligand binding free energy are highly conserved in evolution. In addition, the electrostatic analysis showed that the closed conformation has stronger long-range electrostatic attraction to the ligand compared with the open conformation. The difference is caused by the rearrangement of several charged residues during the binding. These observations make us suggest that the integrin [Formula: see text]2-I domain binding process involves the two-step “dock-lock” mechanism. The closed conformation first attracts the ligand from a long distance and afterwards, the open conformation locks the ligand at the binding site with high binding affinity.
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GUYEUX, CHRISTOPHE, NATHALIE M. L. CÔTÉ, JACQUES M. BAHI, and WOJCIECH BIENIA. "IS PROTEIN FOLDING PROBLEM REALLY A NP-COMPLETE ONE? FIRST INVESTIGATIONS." Journal of Bioinformatics and Computational Biology 12, no. 01 (January 28, 2014): 1350017. http://dx.doi.org/10.1142/s0219720013500170.
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To determine the 3D conformation of proteins is a necessity to understand their functions or interactions with other molecules. It is commonly admitted that, when proteins fold from their primary linear structures to their final 3D conformations, they tend to choose the ones that minimize their free energy. To find the 3D conformation of a protein knowing its amino acid sequence, bioinformaticians use various models of different resolutions and artificial intelligence tools, as the protein folding prediction problem is a NP complete one. More precisely, to determine the backbone structure of the protein using the low resolution models (2D HP square and 3D HP cubic), by finding the conformation that minimizes free energy, is intractable exactly. Both proofs of NP-completeness and the 2D prediction consider that acceptable conformations have to satisfy a self-avoiding walk (SAW) requirement, as two different amino acids cannot occupy a same position in the lattice. It is shown in this document that the SAW requirement considered when proving NP-completeness is different from the SAW requirement used in various prediction programs, and that they are different from the real biological requirement. Indeed, the proof of NP completeness and the predictions in silico consider conformations that are not possible in practice. Consequences of this fact are investigated in this research work.
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Cox, D. H., J. Cui, and R. W. Aldrich. "Allosteric Gating of a Large Conductance Ca-activated K+ Channel." Journal of General Physiology 110, no. 3 (September 1, 1997): 257–81. http://dx.doi.org/10.1085/jgp.110.3.257.
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Large-conductance Ca-activated potassium channels (BK channels) are uniquely sensitive to both membrane potential and intracellular Ca2+. Recent work has demonstrated that in the gating of these channels there are voltage-sensitive steps that are separate from Ca2+ binding steps. Based on this result and the macroscopic steady state and kinetic properties of the cloned BK channel mslo, we have recently proposed a general kinetic scheme to describe the interaction between voltage and Ca2+ in the gating of the mslo channel (Cui, J., D.H. Cox, and R.W. Aldrich. 1997. J. Gen. Physiol. In press.). This scheme supposes that the channel exists in two main conformations, closed and open. The conformational change between closed and open is voltage dependent. Ca2+ binds to both the closed and open conformations, but on average binds more tightly to the open conformation and thereby promotes channel opening. Here we describe the basic properties of models of this form and test their ability to mimic mslo macroscopic steady state and kinetic behavior. The simplest form of this scheme corresponds to a voltage-dependent version of the Monod-Wyman-Changeux (MWC) model of allosteric proteins. The success of voltage-dependent MWC models in describing many aspects of mslo gating suggests that these channels may share a common molecular mechanism with other allosteric proteins whose behaviors have been modeled using the MWC formalism. We also demonstrate how this scheme can arise as a simplification of a more complex scheme that is based on the premise that the channel is a homotetramer with a single Ca2+ binding site and a single voltage sensor in each subunit. Aspects of the mslo data not well fitted by the simplified scheme will likely be better accounted for by this more general scheme. The kinetic schemes discussed in this paper may be useful in interpreting the effects of BK channel modifications or mutations.
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del Alamo, Diego, Kevin L. Jagessar, Jens Meiler, and Hassane S. Mchaourab. "Methodology for rigorous modeling of protein conformational changes by Rosetta using DEER Distance Restraints." PLOS Computational Biology 17, no. 6 (June 16, 2021): e1009107. http://dx.doi.org/10.1371/journal.pcbi.1009107.
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We describe an approach for integrating distance restraints from Double Electron-Electron Resonance (DEER) spectroscopy into Rosetta with the purpose of modeling alternative protein conformations from an initial experimental structure. Fundamental to this approach is a multilateration algorithm that harnesses sets of interconnected spin label pairs to identify optimal rotamer ensembles at each residue that fit the DEER decay in the time domain. Benchmarked relative to data analysis packages, the algorithm yields comparable distance distributions with the advantage that fitting the DEER decay and rotamer ensemble optimization are coupled. We demonstrate this approach by modeling the protonation-dependent transition of the multidrug transporter PfMATE to an inward facing conformation with a deviation to the experimental structure of less than 2Å Cα RMSD. By decreasing spin label rotamer entropy, this approach engenders more accurate Rosetta models that are also more closely clustered, thus setting the stage for more robust modeling of protein conformational changes.
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Vank, Judith C., Carlos P. Sosa, Andras Perczel, and Imre G. Csizmadia. "Peptide models XXVII. An exploratory ab initio study on the 21st amino acid side-chain conformations of N-formyl-L-selenocysteinamide (For-L-Sec-NH2) and N-acetyl-L-selenocysteine-N-methylamide (Ac-L-Sec-NHMe) in their γL backbone conformation." Canadian Journal of Chemistry 78, no. 3 (March 1, 2000): 395–408. http://dx.doi.org/10.1139/v00-029.
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Selenocysteine is expected to have 9 × 9 = 81 conformations [3 × 3 = 9 backbone: ψ (g+,a,g-) × ϕ (g+,a,g-) and 3 × 3 = 9 side-chain: χ1 (g+,a,g-) × χ2 (g+,a,g-)]. In the present study, all the torsional modes of the side-chain (χ1: rotation about the Cα-Cβ and χ2: rotation about the Cβ-Se bonds) were investigated in the relaxed γL backbone [(ϕ,ψ); (g-,g+)] conformation. Seven out of the nine expected minima were found at the RHF/3-21G level of theory for N-formyl-L-selenocysteinamide (For-L-Sec-NH2) and N-acetyl-L-selenocysteine-N-methylamide (Ac-L-Sec-NHMe). The stabilization energy exerted by the -CH2-SeH side-chain has been compared with that of -CH2-SH and -CH2-OH. Relative energies of the various conformers were also obtained via single point calculations at the B3LYP/6-31G(d,p) level of theory. Topological analysis of the electron density has been performed by Bader's Atoms in Molecule (AIM) approach using the results. The structures were also optimized at the B3LYP/6-31+G(d,p) level of theory.Key words: selenocysteine side-chain conformations, ab initio MO study, Multidimensional Conformational Analysis (MDCA), Atoms in Molecules (AIM), Bader's electron density analysis.
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Corne, Valeria, Ariel M. Sarotti, Carmen Ramirez de Arellano, Rolando A. Spanevello, and Alejandra G. Suárez. "Experimental and theoretical insights in the alkene–arene intramolecular π-stacking interaction." Beilstein Journal of Organic Chemistry 12 (July 28, 2016): 1616–23. http://dx.doi.org/10.3762/bjoc.12.158.
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Chiral acrylic esters derived from biomass were developed as models to have a better insight in the aryl–vinyl π-stacking interactions. Quantum chemical calculations, NMR studies and experimental evidences demonstrated the presence of equilibriums of at least four different conformations: π-stacked and face-to-edge, each of them in an s-cis/s-trans conformation. The results show that the stabilization produced by the π–π interaction makes the π-stacked conformation predominant in solution and this stabilization is slightly affected by the electron density of the aromatic counterpart.
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Mountassif, Driss, Lucien Fabre, Kaustuv Basu, Mihnea Bostina, Slavica Jonic, and Isabelle Rouiller. "Conformational heterogeneity of the AAA ATPase p97 characterized by single particle cryo-EM." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C853. http://dx.doi.org/10.1107/s2053273314091463.
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p97, a member of the AAA (ATPase Associated with various Activities) ATPase family, is essential and centrally involved in a wide variety of cellular processes. Single amino-acid substitutions in p97 have been associated with the severe degenerative disorder of Inclusion Body Myopathy associated with Paget disease of bone and Frontotemporal Dementia (IBMPFD) as well as amytropic leteral sclerosis (ALS). Current models propose that p97 acts as a motor transmitting the energy from the ATPase cycle to conformational changes of substrate protein complexes causing segregation, remodeling or translocation. Mutations at the interface between the N and the D1 domains impact the ATPase activity and the conformation of D2 on the opposite side of the protein complex, suggesting intermolecular communication. Because of limited structural information, the molecular mechanisms on how p97 drives its activities and the molecular basis for transmission of information within the molecule remain elusive. Structural heterogeneity is observed in vitro and is likely relevant for the in vivo biological function of p97. Single particle cryo-EM is the method of choice to study a flexible complex. The technique allows study in solution and also deals with sample heterogeneity by image classification. We have set-up the characterization of the conformational heterogeneity in WT and disease relevant p97 mutant using multi-likelihood classification and Hybrid Electron Microscopy Normal Mode Analysis HEMNMA. The multi-likelihood analysis shows a link between the conformations of the N and D2 domains. HEMNMA allows the analysis of the asymmetry of the conformational changes. Together these studies describe the structural flexibility of p97 and the coupling of the ATPase activity with conformational changes in health and in disease. Study of this model system also allows the development of new methods to understand the conformational heterogeneity of other protein complexes.
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Koide, Hiroki, Noriyuki Kodera, Shveta Bisht, Shoji Takada, and Tsuyoshi Terakawa. "Modeling of DNA binding to the condensin hinge domain using molecular dynamics simulations guided by atomic force microscopy." PLOS Computational Biology 17, no. 7 (July 30, 2021): e1009265. http://dx.doi.org/10.1371/journal.pcbi.1009265.
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The condensin protein complex compacts chromatin during mitosis using its DNA-loop extrusion activity. Previous studies proposed scrunching and loop-capture models as molecular mechanisms for the loop extrusion process, both of which assume the binding of double-strand (ds) DNA to the hinge domain formed at the interface of the condensin subunits Smc2 and Smc4. However, how the hinge domain contacts dsDNA has remained unknown. Here, we conducted atomic force microscopy imaging of the budding yeast condensin holo-complex and used this data as basis for coarse-grained molecular dynamics simulations to model the hinge structure in a transient open conformation. We then simulated the dsDNA binding to open and closed hinge conformations, predicting that dsDNA binds to the outside surface when closed and to the outside and inside surfaces when open. Our simulations also suggested that the hinge can close around dsDNA bound to the inside surface. Based on these simulation results, we speculate that the conformational change of the hinge domain might be essential for the dsDNA binding regulation and play roles in condensin-mediated DNA-loop extrusion.
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Nicholls, Robert A., Marcus Fischer, Stuart McNicholas, and Garib N. Murshudov. "Conformation-independent structural comparison of macromolecules withProSMART." Acta Crystallographica Section D Biological Crystallography 70, no. 9 (August 29, 2014): 2487–99. http://dx.doi.org/10.1107/s1399004714016241.
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The identification and exploration of (dis)similarities between macromolecular structures can help to gain biological insight, for instance when visualizing or quantifying the response of a protein to ligand binding. Obtaining a residue alignment between compared structures is often a prerequisite for such comparative analysis. If the conformational change of the protein is dramatic, conventional alignment methods may struggle to provide an intuitive solution for straightforward analysis. To make such analyses more accessible, theProcrustes Structural Matching Alignment and Restraints Tool(ProSMART) has been developed, which achieves a conformation-independent structural alignment, as well as providing such additional functionalities as the generation of restraints for use in the refinement of macromolecular models. Sensible comparison of protein (or DNA/RNA) structures in the presence of conformational changes is achieved by enforcing neither chain nor domain rigidity. The visualization of results is facilitated by popular molecular-graphics software such asCCP4mgandPyMOL, providing intuitive feedback regarding structural conservation and subtle dissimilarities between close homologues that can otherwise be hard to identify. Automatically generated colour schemes corresponding to various residue-based scores are provided, which allow the assessment of the conservation of backbone and side-chain conformations relative to the local coordinate frame. Structural comparison tools such asProSMARTcan help to break the complexity that accompanies the constantly growing pool of structural data into a more readily accessible form, potentially offering biological insight or influencing subsequent experiments.
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Tronrud, Dale, and P. Karplus. "The Protein Geometry Database: exploring protein conformational features." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C499. http://dx.doi.org/10.1107/s205327331409500x.
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Have you ever seen a feature in your structure and asked, "I wonder how novel this is?" For instance a residue with a certain phi/psi angle, or an Asp residue followed by three further residues that make a tight turn centered on the side chain, or a peptide unit deviating 25° from planarity? If so, the Protein Geometry Database (PGD) is something you'll want to know about. The PGD web service (pgd.science.oregonstate.edu, Berkholz 2009a) manages access to a database containing the geometric details of 1.9 million amino acids. Working with the PGD involves two easy steps - using a search form to find a set of peptides matching your interests, and analyzing the geometric details of the set. The search form allows you to find examples of peptide fragments that have any specified combination of backbone conformations and sequence. Filtering can also be performed based on side chain conformations, or bond angles. You can also specify the quality of models included in the search. Once a set of peptides has been identified, their geometric properties can be analyzed on the web site. You can look at the averages and standard deviations for any bond length, bond angle, or conformational angle, or you can explore relationships between properties by displaying highly customizable plots. An option to export the search results allows you to perform any further analyses you might devise. We will show how the PGD has been used to develop a Conformation Dependent Library of main chain bond angle targets for crystallographic refinement (Berkholz 2009b), as well as to advance our understanding of peptide non-planarity, and of conformational preferences for pairs of residues and of cis-peptides. We will also describe how simple searches for outliers in bond lengths and angles are a powerful validation tool that can both uncovering errors in PDB models and can lead to the discovery of very interesting and real deviations from what is normally considered ideal geometry.
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Gorraitz, Edurne, Bruce A. Hirayama, Aviv Paz, Ernest M. Wright, and Donald D. F. Loo. "Active site voltage clamp fluorometry of the sodium glucose cotransporter hSGLT1." Proceedings of the National Academy of Sciences 114, no. 46 (October 30, 2017): E9980—E9988. http://dx.doi.org/10.1073/pnas.1713899114.
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In the human sodium glucose cotransporter (hSGLT1) cycle, the protein undergoes conformational changes where the sugar-binding site alternatively faces the external and internal surfaces. Functional site-directed fluorometry was used to probe the conformational changes at the sugar-binding site. Residues (Y290, T287, H83, and N78) were mutated to cysteines. The mutants were expressed in Xenopus laevis oocytes and tagged with environmentally sensitive fluorescent rhodamines [e.g., tetramethylrhodamine (TMR)-thiols]. The fluorescence intensity was recorded as the mutants were driven into different conformations using voltage jumps. Sugar binding and transport by the fluorophore-tagged mutants were blocked, but Na+ binding and the voltage-dependent conformational transitions were unaffected. Structural models indicated that external Na+ binding opened a large aqueous vestibule (600 Å3) leading to the sugar-binding site. The fluorescence of TMR covalently linked to Y290C, T287C, and H83C decreased as the mutant proteins were driven from the inward to the outward open Na+-bound conformation. The time courses of fluorescence changes (milliseconds) were close to the SGLT1 capacitive charge movements. The quench in rhodamine fluorescence indicated that the environment of the chromophores became more polar with opening of the external gates as the protein transitioned from the inward to outward facing state. Structural analyses showed an increase in polar side chains and a decrease in hydrophobic side chains lining the vestibule, and this was reflected in solvation of the chromophore. The results demonstrate the opening and closing of external gates in real time, with the accompanying changes of polarity of the sugar vestibule.
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Fields, Peter A., Yong-Sung Kim, John F. Carpenter, and George N. Somero. "Temperature adaptation in Gillichthys (Teleost: Gobiidae)A4-lactate dehydrogenases." Journal of Experimental Biology 205, no. 9 (May 1, 2002): 1293–303. http://dx.doi.org/10.1242/jeb.205.9.1293.
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SUMMARY Alternative conformations of proteins underlie a variety of biological phenomena, from prion proteins that cause spongiform encephalopathies to membrane channel proteins whose conformational changes admit or exclude specific ions. In this paper, we argue that conformational differences within globular `housekeeping' enzymes may allow rapid adaptation to novel environments. Muscle-type lactate dehydrogenases (A4-LDHs) from the gobies Gillichthys seta and G. mirabilis have identical amino acid sequences but show potentially adaptive differences in substrate affinity (apparent Michaelis constants for pyruvate, KmPYR) as well as differences in thermal stability. We examined the A4-LDH of each species using fluorescence spectroscopy, near- and far-ultraviolet circular dichroism (CD)spectroscopy and hydrogen/deuterium exchange (H/D) Fourier-transform infrared spectroscopy to determine whether structural differences were apparent, the extent to which structural differences could be related to differences in conformational flexibility and whether specific changes in secondary or tertiary structure could be defined. The fluorescence spectra and far-ultraviolet CD spectra of the A4-LDH from the two species were indistinguishable, suggesting that the two conformations are very similar in secondary and tertiary structure. Apparent melting temperatures(Tm) followed by fluorescence and CD spectroscopy confirmed that the G. mirabilis A4-LDH is more thermally stable than the G. seta form. H/D exchange kinetics of Gillichthys A4-LDH was described using double-exponential regression; at 20 °C, G. seta A4-LDH has a higher exchange constant, indicating a more flexible and open structure. At 40°C, the difference in H/D exchange constants disappears. Second-derivative analysis of H/D exchange infrared spectra indicates that α-helical, but not β-sheet structure, differs in conformational flexibility between the two forms. Second-derivative ultraviolet spectra indicate that at least one of the five tyrosyl residues in the Gillichthys LDH-A monomer is located in a more hydrophobic environment in the G. mirabilis form. Homology models of A4-LDH indicate that Tyr246 is the most likely candidate to experience a modified environment because it is involved in subunit contacts within the homotetramer and sits in a hinge between a staticα-helix and one involved in catalytic conformational changes. Subtle differences in conformation around this residue probably play a role both in altered flexibility and in the potentially adaptive differences in kinetics between the two A4-LDH forms.
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London, Nir, and Ora Schueler-Furman. "FunHunt: model selection based on energy landscape characteristics." Biochemical Society Transactions 36, no. 6 (November 19, 2008): 1418–21. http://dx.doi.org/10.1042/bst0361418.
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Protein folding and binding is commonly depicted as a search for the minimum energy conformation in a vast energy landscape. Indeed, modelling of protein complex structures by RosettaDock often results in a set of low-energy conformations near the native structure. Ensembles of low-energy conformations can appear, however, in other regions of the energy landscape, especially when backbone movements occur upon binding. What then characterizes the energy landscape near the correct orientation? We have applied a machine learning algorithm to distinguish ensembles of low-energy conformations around the native conformation from other low-energy ensembles. FunHunt, the resulting classifier, identified the native orientation for 50/52 protein complexes in a test set, and for all of 12 recent CAPRI targets. FunHunt is also able to choose the near-native orientation among models created by algorithms other than RosettaDock, demonstrating its general applicability for model selection. The features used by FunHunt teach us about the nature of native interfaces. Remarkably, the energy decrease of trajectories toward near-native orientations is significantly larger than for other orientations. This provides a possible explanation for the stability of association in the native orientation. The FunHunt approach, discriminating models based on ensembles of structures that map the nearby energy landscape, can be adapted and extended to additional tasks, such as ab initio model selection, protein interface design and specificity predictions.
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Buchanan, G. W., A. Moghimi, V. M. Reynolds, and K. Bourque. "Dicyclohexylethyleneglycol, -diethyleneglycol, -triethyleneglycol, and related monosubstituted cyclohexanes. Conformational analysis using low-temperature 13C and 1H NMR spectroscopy." Canadian Journal of Chemistry 73, no. 4 (April 1, 1995): 566–72. http://dx.doi.org/10.1139/v95-073.
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Two conformations of each of the title molecules have been detected by 100 MHz 13C NMR at 210 K. For the dicyclohexyl systems, the conformations are related via a single ring inversion. In each case the equatorial–axial conformer is 4.7 ± 0.4 kJ/mol less stable than the diequatorially substituted form in CD2Cl2 solution. For monosubstituted models, the conformational free energy (−ΔG0) values of the -O-CH2-CH2-OCH3, -OCH2-CH2-O-CH2-CH3, and -O-CH2-CH2-O-CH-(CH3)2 groups have been determined to be 5.4,6.1, and 6.1 ± 0.2 kJ/mol, respectively. In methanol, the latter equilibria are slightly more biased towards the axially substituted conformers. Keywords: substituted ethylene glycols, conformational equilibria.
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Starmer, C. F., V. V. Nesterenko, F. R. Gilliam, and A. O. Grant. "Use of ionic currents to identify and estimate parameters in models of channel blockade." American Journal of Physiology-Heart and Circulatory Physiology 259, no. 2 (August 1, 1990): H626—H634. http://dx.doi.org/10.1152/ajpheart.1990.259.2.h626.
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Models of ion channel blockade are frequently validated with observations of ionic currents resulting from electrical or chemical stimulation. Model parameters for some models (modulated receptor hypothesis) cannot be uniquely determined from ionic currents. The time course of ionic currents reflects the activation (fraction of available channels that conduct in the presence of excitation) and availability of channels (the ability of the protein to make a transition to a conducting conformation and where this conformation is not complexed with a drug). In the presence of a channel blocking agent, the voltage dependence of availability appears modified and has been interpreted as evidence that drug-complexed channels exhibit modified transition rates between channel protein conformations. Because blockade and availability both modify ionic currents, their individual contributions to macroscopic conductance cannot be resolved from ionic currents except when constant affinity binding to a bindable site is assumed. Experimental studies of nimodipine block of calcium channels and lidocaine block of sodium channels illustrate these concepts.
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Jangra, Harish, Michael H. Haindl, Florian Achrainer, Johnny Hioe, Ruth M. Gschwind, and Hendrik Zipse. "Conformational Preferences in Small Peptide Models: The Relevance ofcis/trans-Conformations." Chemistry - A European Journal 22, no. 37 (August 18, 2016): 13328–35. http://dx.doi.org/10.1002/chem.201601828.
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Palmer, Allan, Suzie Poulin-Dandurand, and François Brisse. "On the structure of poly(tetramethylene terephthalate). Structural, infrared, and Raman studies of three tetramethylene glycol dibenzoate derivatives, models for poly(tetramethylene terephthalate)." Canadian Journal of Chemistry 63, no. 11 (November 1, 1985): 3079–88. http://dx.doi.org/10.1139/v85-510.
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The crystal structures of tetramethylene glycol dibenzoate (1), tetramethylene glycol di-pora-chlorobenzoate (2), and tetramethylene glycol di-para-nitrobenzoate (3) have been solved by direct methods in order to establish the possible conformations of the methylenic sequence in poly(tetramethylene terephthalate), poly(4GT). Compound 1 has a triclinic unit cell of dimensions a = 7.870(3), b = 8.574(3), c = 12.993(4) Å α = 83.76(3), β = 89.92(3), γ = 64.68(3)°; Z = 2, space group [Formula: see text]. For 2 the unit cell is also triclinic and has dimensions a = 5.916(3), b = 7.599(2), c = 10.404(2) Å; α = 67.81(2), β = 77.47(2), γ = 81.63(3)°; Z = 1, space group [Formula: see text]. The unit cell dimensions of 3 are a = 6.086(1), b = 11.475(3), c = 13.162(3) Å and β = 101.93(2)°, Z = 2. The space group is P21/c. The structures were solved by direct methods using 2682, 969, and 781 observed reflections for 1, 2, and 3, respectively. The refinements were concluded when R reached the values of 0.042, 0.046, and 0.045, respectively. The conformation of the methylenic sequence varies depending on the substituent on the benzoate group. The conformation observed in 1 is tg−t t t, it is t t t t t for 2, and tg−tgt for 3 (t = trans, g = gauche). Although the equivalent fiber repeat of 3 coincides with the observed fiber repeat for α-poly(4GT), this does not imply that 3 and α-poly(4GT) have the same conformation. Compound 2 allows for the modelling of the β-form of poly(4GT). However, this does not lead to a clear choice between the two structures reported for this form. The two distinct conformations proposed for the β-form of poly(4GT) are distinguished on the basis of their ir and Raman spectra. The comparison of the spectra of the model compounds reveals that, in ir, for an all-trans conformation there is no absorption band at 1383 cm−1 but one is present at 1395 cm−1. This situation that is observed in the ir spectra of β-poly(4GT) led us to propose that this form has the all-trans conformation as proposed by Hall and Pass. This choice is further supported by the presence of three bands at 1047, 1347, and 1405 cm−1 in the Raman spectra of β-poly(4GT). These three bands are only observed in the model compounds having the all-trans conformation.
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Luque, Daniel, Irene Saugar, José F. Rodríguez, Nuria Verdaguer, Damiá Garriga, Carmen San Martín, Javier A. Velázquez-Muriel, Benes L. Trus, José L. Carrascosa, and José R. Castón. "Infectious Bursal Disease Virus Capsid Assembly and Maturation by Structural Rearrangements of a Transient Molecular Switch." Journal of Virology 81, no. 13 (April 18, 2007): 6869–78. http://dx.doi.org/10.1128/jvi.00077-07.
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ABSTRACT Infectious bursal disease virus (IBDV), a double-stranded RNA (dsRNA) virus belonging to the Birnaviridae family, is an economically important avian pathogen. The IBDV capsid is based on a single-shelled T=13 lattice, and the only structural subunits are VP2 trimers. During capsid assembly, VP2 is synthesized as a protein precursor, called pVP2, whose 71-residue C-terminal end is proteolytically processed. The conformational flexibility of pVP2 is due to an amphipathic α-helix located at its C-terminal end. VP3, the other IBDV major structural protein that accomplishes numerous roles during the viral cycle, acts as a scaffolding protein required for assembly control. Here we address the molecular mechanism that defines the multimeric state of the capsid protein as hexamers or pentamers. We used a combination of three-dimensional cryo-electron microscopy maps at or close to subnanometer resolution with atomic models. Our studies suggest that the key polypeptide element, the C-terminal amphipathic α-helix, which acts as a transient conformational switch, is bound to the flexible VP2 C-terminal end. In addition, capsid protein oligomerization is also controlled by the progressive trimming of its C-terminal domain. The coordination of these molecular events correlates viral capsid assembly with different conformations of the amphipathic α-helix in the precursor capsid, as a five-α-helix bundle at the pentamers or an open star-like conformation at the hexamers. These results, reminiscent of the assembly pathway of positive single-stranded RNA viruses, such as nodavirus and tetravirus, add new insights into the evolutionary relationships of dsRNA viruses.
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Sun, Jixue, Zibin Li, and Na Yang. "Mechanism of the Conformational Change of the Protein Methyltransferase SMYD3: A Molecular Dynamics Simulation Study." International Journal of Molecular Sciences 22, no. 13 (July 2, 2021): 7185. http://dx.doi.org/10.3390/ijms22137185.
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SMYD3 is a SET-domain-containing methyltransferase that catalyzes the transfer of methyl groups onto lysine residues of substrate proteins. Methylation of MAP3K2 by SMYD3 has been implicated in Ras-driven tumorigenesis, which makes SMYD3 a potential target for cancer therapy. Of all SMYD family proteins, SMYD3 adopt a closed conformation in a crystal structure. Several studies have suggested that the conformational changes between the open and closed forms may regulate the catalytic activity of SMYD3. In this work, we carried out extensive molecular dynamics simulations on a series of complexes with a total of 21 μs sampling to investigate the conformational changes of SMYD3 and unveil the molecular mechanisms. Based on the C-terminal domain movements, the simulated models could be depicted in three different conformational states: the closed, intermediate and open states. Only in the case that both the methyl donor binding pocket and the target lysine-binding channel had bound species did the simulations show SMYD3 maintaining its conformation in the closed state, indicative of a synergetic effect of the cofactors and target lysine on regulating the conformational change of SMYD3. In addition, we performed analyses in terms of structure and energy to shed light on how the two regions might regulate the C-terminal domain movement. This mechanistic study provided insights into the relationship between the conformational change and the methyltransferase activity of SMYD3. The more complete understanding of the conformational dynamics developed here together with further work may lay a foundation for the rational drug design of SMYD3 inhibitors.
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Chan, Bun, and Leo Radom. "Modelling the Effect of Conformation on Hydrogen-Atom Abstraction from Peptides." Australian Journal of Chemistry 71, no. 4 (2018): 257. http://dx.doi.org/10.1071/ch17621.
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Computational quantum chemistry is used to examine the effect of conformation on the kinetics of hydrogen-atom abstraction by HO• from amides of glycine and proline as peptide models. In accord with previous findings, it is found that there are substantial variations possible in the conformations and the corresponding energies, with the captodative effect, hydrogen bonding, and solvation being some of the major features that contribute to the variations. The ‘minimum-energy-structure-pathway’ strategy that is often employed in theoretical studies of peptide chemistry with small models certainly provides valuable fundamental information. However, one may anticipate different reaction outcomes in structurally constrained systems due to modified reaction thermodynamics and kinetics, as demonstrated explicitly in the present study. Thus, using a ‘consistent-conformation-pathway’ approach may indeed be more informative in such circumstances, and in this regard theory provides information that would be difficult to obtain from experimental studies alone.
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OLSON, BRIAN, KEVIN MOLLOY, and AMARDA SHEHU. "IN SEARCH OF THE PROTEIN NATIVE STATE WITH A PROBABILISTIC SAMPLING APPROACH." Journal of Bioinformatics and Computational Biology 09, no. 03 (June 2011): 383–98. http://dx.doi.org/10.1142/s0219720011005574.
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The three-dimensional structure of a protein is a key determinant of its biological function. Given the cost and time required to acquire this structure through experimental means, computational models are necessary to complement wet-lab efforts. Many computational techniques exist for navigating the high-dimensional protein conformational search space, which is explored for low-energy conformations that comprise a protein's native states. This work proposes two strategies to enhance the sampling of conformations near the native state. An enhanced fragment library with greater structural diversity is used to expand the search space in the context of fragment-based assembly. To manage the increased complexity of the search space, only a representative subset of the sampled conformations is retained to further guide the search towards the native state. Our results make the case that these two strategies greatly enhance the sampling of the conformational space near the native state. A detailed comparative analysis shows that our approach performs as well as state-of-the-art ab initio structure prediction protocols.
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Kim, J. I., K. Eom, and S. Na. "Mechanical Mass-Spring Model for Understanding Globular Motion of Proteins." Journal of Mechanics 32, no. 2 (January 25, 2016): 123–29. http://dx.doi.org/10.1017/jmech.2015.109.
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AbstractThe conformational (structural) change of proteins plays an essential role in their functions. Experiments have been conducted to try to understand the conformational change of proteins, but they have not been successful in providing information on the atomic scale. Simulation methods have been developed to understand the conformational change at an atomic scale in detail. Coarse-grained methods have been developed to calculate protein dynamics with computational efficiency when compared with than all-atom models. A structure-based mass-spring model called the elastic network model (ENM) showed excellent performance in various protein studies. Coarse-grained ENM was modified in various ways to improve the computational efficiency, and consequently to reduce required computational cost for studying the large-scale protein structures. Our previous studies report a modified mass-spring model, which was developed based on condensation method applicable to ENM, and show that the model is able to accurately predict the fluctuation behavior of proteins. We applied this modified mass-spring model to analyze the conformational changes in proteins. We consider two model proteins as an example, where these two proteins exhibit different functions and molecular sizes. It is shown that the modified mass-spring model allows for accurately predicting the pathways of conformation changes for proteins. Our model provides structural insights into the conformation change of proteins related to the biological functions of large protein complexes.
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Porebski, Przemyslaw Jerzy, Marcin Cymborowski, Marta Pasenkiewicz-Gierula, and Wladek Minor. "Fitmunk: improving protein structures by accurate, automatic modeling of side-chain conformations." Acta Crystallographica Section D Structural Biology 72, no. 2 (January 28, 2016): 266–80. http://dx.doi.org/10.1107/s2059798315024730.
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Improvements in crystallographic hardware and software have allowed automated structure-solution pipelines to approach a near-`one-click' experience for the initial determination of macromolecular structures. However, in many cases the resulting initial model requires a laborious, iterative process of refinement and validation. A new method has been developed for the automatic modeling of side-chain conformations that takes advantage of rotamer-prediction methods in a crystallographic context. The algorithm, which is based on deterministic dead-end elimination (DEE) theory, uses new dense conformer libraries and a hybrid energy function derived from experimental data and prior information about rotamer frequencies to find the optimal conformation of each side chain. In contrast to existing methods, which incorporate the electron-density term into protein-modeling frameworks, the proposed algorithm is designed to take advantage of the highly discriminatory nature of electron-density maps. This method has been implemented in the programFitmunk, which uses extensive conformational sampling. This improves the accuracy of the modeling and makes it a versatile tool for crystallographic model building, refinement and validation.Fitmunkwas extensively tested on over 115 new structures, as well as a subset of 1100 structures from the PDB. It is demonstrated that the ability ofFitmunkto model more than 95% of side chains accurately is beneficial for improving the quality of crystallographic protein models, especially at medium and low resolutions.Fitmunkcan be used for model validation of existing structures and as a tool to assess whether side chains are modeled optimally or could be better fitted into electron density.Fitmunkis available as a web service at http://kniahini.med.virginia.edu/fitmunk/server/ or at http://fitmunk.bitbucket.org/.
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Manley, Paul W., Sandra W. Cowan-Jacob, Gabriele Fendrich, André Strauss, Navratna Vapai, Stephan Grzesiek, and Wolfgang Jahnke. "Bcr-Abl Binding Modes of Dasatinib, Imatinib and Nilotinib: An NMR Study." Blood 108, no. 11 (November 16, 2006): 747. http://dx.doi.org/10.1182/blood.v108.11.747.747.
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Abstract Following the discovery that point mutations in the kinase domain of Bcr-Abl reduce the binding affinity of imatinib and lead to drug resistance in CML patients, efforts have been directed towards the discovery of new drugs which inhibit these resistant enzymes. Two such agents are dasatinib and nilotinib. Whereas, like imatinib, x-ray analysis of crystal structures of nilotinib in complex with the Abl kinase domain reveal that this agent binds to an inactive, DFG-out conformation of the enzyme, similar studies have shown that dasatinib binds to the catalytically active state of the enzyme (Tokarski et al, Cancer Res. 2006). However, based upon in silico methods using homology models of the imatinib-binding inactive conformation of Abl some reports claim that dasatinib is capable of binding to both the active and inactive forms of the enzyme. To help address this conundrum we have employed nuclear magnetic resonance (NMR) spectroscopy to study the different conformational characteristics and dynamic changes of the Abl protein obtained upon adding ligands. Selectively isotope labelled (15N and 13C) Abl kinase in the unphosphorylated state was produced according to published methods (Strauss et al, J. Biomolecular NMR 2005). Chemical shift data of the protein in solution were recorded by NMR spectroscopy, both with and without ligand. By measuring residual dipolar couplings (RDC) between the back-bone amide nitrogen and hydrogen atoms of amino-acid residues in the vicinity of the conserved DFG-motif (residues 370 – 410), the conformational states and equilibria of the activation loop of the kinase were established. Upon adding imatinib to the unliganded Abl, both chemical shift and RDC data show characteristic signals for residues M388, Y393 and G398, which are entirely consistent with the conformational equilibrium moving to the inactive state, in which the activation loop adopts the DFG-out conformation. In the case of nilotinib, NMR spectroscopy revealed chemical shift patterns and couplings involving the same three residues confirming that the drug binds to the same inactive conformation as imatinib, both in solution as well as in the crystalline state. In contrast, upon adding dasatinib to Abl, NMR data of the complex show distinctly different chemical shifts and RDC values, confirming that the protein assumes a different conformational state, with the activation loop adopting the active conformation, in accordance with the crystallographic evidence. Even upon adding dasatinib to a complex of imatinib with Abl in the inactive conformation, the kinase conformation changed to a state indistinguishable to that observed upon adding dasatinib to unliganded protein. In conclusion, these studies show that the three Abl kinase inhibitors all interact with the protein in solution with the same binding modes as observed in x-ray crystallographic studies, but show no evidence for dasatinib binding to the inactive “DFG-out” conformation. This case study also demonstrates the power of NMR spectroscopy in evaluating solution structures of ligand-protein complexes. Further experiments are in progress evaluating other structurally different Abl kinase inhibitors.
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Blanco Capurro, Juan I., Matias Di Paola, Marcelo Daniel Gamarra, Marcelo A. Martí, and Carlos P. Modenutti. "An efficient use of X-ray information, homology modeling, molecular dynamics and knowledge-based docking techniques to predict protein–monosaccharide complexes." Glycobiology 29, no. 2 (November 8, 2018): 124–36. http://dx.doi.org/10.1093/glycob/cwy102.
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Abstract Unraveling the structure of lectin–carbohydrate complexes is vital for understanding key biological recognition processes and development of glycomimetic drugs. Molecular Docking application to predict them is challenging due to their low affinity, hydrophilic nature and ligand conformational diversity. In the last decade several strategies, such as the inclusion of glycan conformation specific scoring functions or our developed solvent-site biased method, have improved carbohydrate docking performance but significant challenges remain, in particular, those related to receptor conformational diversity. In the present work we have analyzed conventional and solvent-site biased autodock4 performance concerning receptor conformational diversity as derived from different crystal structures (apo and holo), Molecular Dynamics snapshots and Homology-based models, for 14 different lectin–monosaccharide complexes. Our results show that both conventional and biased docking yield accurate lectin–monosaccharide complexes, starting from either apo or homology-based structures, even when only moderate (45%) sequence identity templates are available. An essential element for success is a proper combination of a middle-sized (10–100 structures) conformational ensemble, derived either from Molecular dynamics or multiple homology model building. Consistent with our previous works, results show that solvent-site biased methods improve overall performance, but that results are still highly system dependent. Finally, our results also show that docking can select the correct receptor structure within the ensemble, underscoring the relevance of joint evaluation of both ligand pose and receptor conformation.
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CALLEJA, Véronique, Simon M. AMEER-BEG, Borivoj VOJNOVIC, Rudiger WOSCHOLSKI, Julian DOWNWARD, and Banafshé LARIJANI. "Monitoring conformational changes of proteins in cells by fluorescence lifetime imaging microscopy." Biochemical Journal 372, no. 1 (May 15, 2003): 33–40. http://dx.doi.org/10.1042/bj20030358.
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To be able to detect in situ changes in protein conformation without perturbing the physiological environment would be a major step forward in understanding the precise mechanism occurring in protein interaction. We have developed a novel approach to monitoring conformational changes of proteins in intact cells. A double-labelled fluorescent green fluorescent protein–yellow fluorescent protein (GFP–YFP) fusion protein has been constructed, allowing the exploitation of enhanced-acceptor-fluorescence (EAF)-induced fluorescence resonance energy transfer (FRET). Additionally, a novel fusion partner, YFPdark, has been designed to act as a sterically hindered control for EAF-FRET. Any conformational changes will cause a variation in FRET, which, in turn, is detected by fluorescence lifetime imaging microscopy (‘FLIM’). Protein kinase B (PKB)/Akt, a key component of phosphoinositide 3-kinase-mediated signalling, was selected for this purpose. Although conformational changes in PKB/Akt consequent to lipid binding and phosphorylation have been proposed in models, its behaviour in intact cells has not been tractable. We report here that platelet-derived-growth-factor (‘PDGF’) stimulation of NIH3T3 cells expressing the GFP–Akt–YFP construct resulted in a loss of FRET at the plasma membrane and hence a change in PKB/Akt conformation. We also show that the GFP–Akt–YFP construct conserves fully its functional integrity. This novel approach of monitoring the in situ conformational changes has broad application for other members of the AGC kinase superfamily and other proteins.
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Tesei, Giulio, João M. Martins, Micha B. A. Kunze, Yong Wang, Ramon Crehuet, and Kresten Lindorff-Larsen. "DEER-PREdict: Software for efficient calculation of spin-labeling EPR and NMR data from conformational ensembles." PLOS Computational Biology 17, no. 1 (January 22, 2021): e1008551. http://dx.doi.org/10.1371/journal.pcbi.1008551.
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Owing to their plasticity, intrinsically disordered and multidomain proteins require descriptions based on multiple conformations, thus calling for techniques and analysis tools that are capable of dealing with conformational ensembles rather than a single protein structure. Here, we introduce DEER-PREdict, a software program to predict Double Electron-Electron Resonance distance distributions as well as Paramagnetic Relaxation Enhancement rates from ensembles of protein conformations. DEER-PREdict uses an established rotamer library approach to describe the paramagnetic probes which are bound covalently to the protein.DEER-PREdict has been designed to operate efficiently on large conformational ensembles, such as those generated by molecular dynamics simulation, to facilitate the validation or refinement of molecular models as well as the interpretation of experimental data. The performance and accuracy of the software is demonstrated with experimentally characterized protein systems: HIV-1 protease, T4 Lysozyme and Acyl-CoA-binding protein. DEER-PREdict is open source (GPLv3) and available at github.com/KULL-Centre/DEERpredict and as a Python PyPI package pypi.org/project/DEERPREdict.
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Askari, Janet A., Christopher J. Tynan, Stephen E. D. Webb, Marisa L. Martin-Fernandez, Christoph Ballestrem, and Martin J. Humphries. "Focal adhesions are sites of integrin extension." Journal of Cell Biology 188, no. 6 (March 15, 2010): 891–903. http://dx.doi.org/10.1083/jcb.200907174.
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Integrins undergo global conformational changes that specify their activation state. Current models portray the inactive receptor in a bent conformation that upon activation converts to a fully extended form in which the integrin subunit leg regions are separated to enable ligand binding and subsequent signaling. To test the applicability of this model in adherent cells, we used a fluorescent resonance energy transfer (FRET)–based approach, in combination with engineered integrin mutants and monoclonal antibody reporters, to image integrin α5β1 conformation. We find that restricting leg separation causes the integrin to adopt a bent conformation that is unable to respond to agonists and mediate cell spreading. By measuring FRET between labeled α5β1 and the cell membrane, we find extended receptors are enriched in focal adhesions compared with adjacent regions of the plasma membrane. These results demonstrate definitely that major quaternary rearrangements of β1-integrin subunits occur in adherent cells and that conversion from a bent to extended form takes place at focal adhesions.
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Zagotta, W. N., T. Hoshi, and R. W. Aldrich. "Shaker potassium channel gating. III: Evaluation of kinetic models for activation." Journal of General Physiology 103, no. 2 (February 1, 1994): 321–62. http://dx.doi.org/10.1085/jgp.103.2.321.
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Predictions of different classes of gating models involving identical conformational changes in each of four subunits were compared to the gating behavior of Shaker potassium channels without N-type inactivation. Each model was tested to see if it could simulate the voltage dependence of the steady state open probability, and the kinetics of the single-channel currents, macroscopic ionic currents and macroscopic gating currents using a single set of parameters. Activation schemes based upon four identical single-step activation processes were found to be incompatible with the experimental results, as were those involving a concerted, opening transition. A model where the opening of the channel requires two conformational changes in each of the four subunits can adequately account for the steady state and kinetic behavior of the channel. In this model, the gating in each subunit is independent except for a stabilization of the open state when all four subunits are activated, and an unstable closed conformation that the channel enters after opening. A small amount of negative cooperativity between the subunits must be added to account quantitatively for the dependence of the activation time course on holding voltage.
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Kim, Tae, and Luke M. Rice. "Long-range, through-lattice coupling improves predictions of microtubule catastrophe." Molecular Biology of the Cell 30, no. 12 (June 2019): 1451–62. http://dx.doi.org/10.1091/mbc.e18-10-0641.
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Microtubules are cylindrical polymers of αβ-tubulin that play critical roles in fundamental processes such as chromosome segregation and vesicular transport. Microtubules display dynamic instability, switching stochastically between growth and rapid shrinking as a consequence of GTPase activity in the lattice. The molecular mechanisms behind microtubule catastrophe, the switch from growth to rapid shrinking, remain poorly defined. Indeed, two-state stochastic models that seek to describe microtubule dynamics purely in terms of the biochemical properties of GTP- and GDP-bound αβ-tubulin predict the concentration dependence of microtubule catastrophe incorrectly. Recent studies provide evidence for three distinct conformations of αβ-tubulin in the lattice that likely correspond to GTP, GDP.Pi, and GDP. The incommensurate lattices observed for these different conformations raise the possibility that in a mixed nucleotide state lattice, neighboring tubulin dimers might modulate each other’s conformations and hence each other’s biochemistry. We explored whether incorporating a GDP.Pistate or the likely effects of conformational accommodation can improve predictions of catastrophe. Adding a GDP.Piintermediate did not improve the model. In contrast, adding neighbor-dependent modulation of tubulin biochemistry improved predictions of catastrophe. Because this conformational accommodation should propagate beyond nearest-neighbor contacts, our modeling suggests that long-range, through-lattice effects are important determinants of microtubule catastrophe.
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Liu, Jun, Xiao-Gen Zhou, Yang Zhang, and Gui-Jun Zhang. "CGLFold: a contact-assisted de novo protein structure prediction using global exploration and loop perturbation sampling algorithm." Bioinformatics 36, no. 8 (December 20, 2019): 2443–50. http://dx.doi.org/10.1093/bioinformatics/btz943.
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Abstract Motivation Regions that connect secondary structure elements in a protein are known as loops, whose slight change will produce dramatic effect on the entire topology. This study investigates whether the accuracy of protein structure prediction can be improved using a loop-specific sampling strategy. Results A novel de novo protein structure prediction method that combines global exploration and loop perturbation is proposed in this study. In the global exploration phase, the fragment recombination and assembly are used to explore the massive conformational space and generate native-like topology. In the loop perturbation phase, a loop-specific local perturbation model is designed to improve the accuracy of the conformation and is solved by differential evolution algorithm. These two phases enable a cooperation between global exploration and local exploitation. The filtered contact information is used to construct the conformation selection model for guiding the sampling. The proposed CGLFold is tested on 145 benchmark proteins, 14 free modeling (FM) targets of CASP13 and 29 FM targets of CASP12. The experimental results show that the loop-specific local perturbation can increase the structure diversity and success rate of conformational update and gradually improve conformation accuracy. CGLFold obtains template modeling score ≥ 0.5 models on 95 standard test proteins, 7 FM targets of CASP13 and 9 FM targets of CASP12. Availability and implementation The source code and executable versions are freely available at https://github.com/iobio-zjut/CGLFold. Supplementary information Supplementary data are available at Bioinformatics online.
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Kajava, A. V. "Dimorphism of polyglycine I: structural models for crystal modifications." Acta Crystallographica Section D Biological Crystallography 55, no. 2 (February 1, 1999): 436–42. http://dx.doi.org/10.1107/s0907444998012438.
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Re-examination of the known data on crystalline forms of polyglycine reveals that the crystal modification `polyglycine I' has two different three-dimensional structures depending on the molecular weight. Structural models for both low molecular weight (LMW) and high molecular weight (HMW) polyglycine I crystals are described. In the LMW crystal model, the molecules have an unusual extended conformation generated by alternation of two mirror-symmetrical residual conformations along the chain. The molecules are parallel and each chain forms interpeptide hydrogen bonds with four adjacent chains. The structural model for the HMW crystal represents a composition of twinning crystallites. The crystallites themselves consist of antiparallel enantiomorphous chains united by hydrogen bonds to form rippled sheets. Calculations of the diffraction patterns and packing energy show that these polyglycine I structures have a higher level of conformity with the experimental data than previously suggested models. New insight into the structure of the polyglycine associates opens up the possibility of designing improved silk-like and nylon materials.
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Yaffe, Dana, Lucy R. Forrest, and Shimon Schuldiner. "The ins and outs of vesicular monoamine transporters." Journal of General Physiology 150, no. 5 (April 17, 2018): 671–82. http://dx.doi.org/10.1085/jgp.201711980.
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The H+-coupled vesicular monoamine transporter (VMAT) is a transporter essential for life. VMAT mediates packaging of the monoamines serotonin, dopamine, norepinephrine, and histamine from the neuronal cytoplasm into presynaptic vesicles, which is a key step in the regulated release of neurotransmitters. However, a detailed understanding of the mechanism of VMAT function has been limited by the lack of availability of high-resolution structural data. In recent years, a series of studies guided by homology models has revealed significant insights into VMAT function, identifying residues that contribute to the binding site and to specific steps in the transport cycle. Moreover, to characterize the conformational transitions that occur upon binding of the substrate and coupling ion, we have taken advantage of the unique and powerful pharmacology of VMAT as well as of mutants that affect the conformational equilibrium of the protein and shift it toward defined conformations. This has allowed us to identify an important role for the proton gradient in driving a shift from lumen-facing to cytoplasm-facing conformations.
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Lyczko, Krzysztof, and Slawomir Ostrowski. "Crystal structures and conformers of CyMe4-BTBP." Nukleonika 60, no. 4 (December 1, 2015): 853–57. http://dx.doi.org/10.1515/nuka-2015-0149.
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Abstract The crystal structure of new conformation of the CyMe4-BTBP ligand (ttc) has been presented. The ttt conformer of this compound in a form of THF solvate has been also crystallized. The geometries of six possible conformations (ttt, ttc, tct, tcc, ctc and ccc) of the CyMe4-BTBP ligand have been modeled in the gas phase and in solutions (MeOH and H2O) by DFT calculations using B3LYP/6-31G(d,p) method. According to the calculations, in the three different media the conformers with trans orientation of the N atoms in the bipyridyl moiety are the most stable.
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Suma, Antonio, Alex Stopar, Allen W. Nicholson, Matteo Castronovo, and Vincenzo Carnevale. "Global and local mechanical properties control endonuclease reactivity of a DNA origami nanostructure." Nucleic Acids Research 48, no. 9 (February 11, 2020): 4672–80. http://dx.doi.org/10.1093/nar/gkaa080.
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Abstract We used coarse-grained molecular dynamics simulations to characterize the global and local mechanical properties of a DNA origami triangle nanostructure. The structure presents two metastable conformations separated by a free energy barrier that is lowered upon omission of four specific DNA staples (defect). In contrast, only one stable conformation is present upon removing eight staples. The metastability is explained in terms of the intrinsic conformations of the three trapezoidal substructures. We computationally modeled the local accessibility to endonucleases, to predict the reactivity of twenty sites, and found good agreement with the experimental data. We showed that global fluctuations affect local reactivity: the removal of the DNA staples increased the computed accessibility to a restriction enzyme, at sites as distant as 40 nm, due to an increase in global fluctuation. These results raise the intriguing possibility of the rational engineering of allosterically modulated DNA origami.
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Popa, Ionel, and Ronen Berkovich. "Mechanobiology: protein refolding under force." Emerging Topics in Life Sciences 2, no. 5 (November 14, 2018): 687–99. http://dx.doi.org/10.1042/etls20180044.
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The application of direct force to a protein enables to probe wide regions of its energy surface through conformational transitions as unfolding, extending, recoiling, collapsing, and refolding. While unfolding under force typically displayed a two-state behavior, refolding under force, from highly extended unfolded states, displayed a more complex behavior. The first recording of protein refolding at a force quench step displayed an initial rapid elastic recoil, followed by a plateau phase at some extension, concluding with a collapse to a final state, at which refolding occurred. These findings stirred a lively discussion, which led to further experimental and theoretical investigation of this behavior. It was demonstrated that the polymeric chain of the unfolded protein is required to fully collapse to a globular conformation for the maturation of native structure. This behavior was modeled using one-dimensional free energy landscape over the end-to-end length reaction coordinate, the collective measured variable. However, at low forces, conformational space is not well captured by such models, and using two-dimensional energy surfaces provides further insight into the dynamics of this process. This work reviews the main concepts of protein refolding under constant force, which is essential for understanding how mechanotransducing proteins operate in vivo.
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Grmela, M., and P. J. Carreau. "Conformation tensor rheological models." Journal of Non-Newtonian Fluid Mechanics 23 (January 1987): 271–94. http://dx.doi.org/10.1016/0377-0257(87)80022-8.
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QUAN, JUN-MIN, and YUN-DONG Wu. "A THEORETICAL STUDY OF THE SUBSTITUENT EFFECT ON THE STABILITY OF COLLAGEN." Journal of Theoretical and Computational Chemistry 03, no. 02 (June 2004): 225–43. http://dx.doi.org/10.1142/s0219633604001008.
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Theoretical calculations have been carried out to investigate the effect of the 4(R)-substituents ( OH , F , NH 2, and [Formula: see text]) in proline on the stability of the collagen triple helix. A series of substituted proline models were studied first with density functional (B3LYP/6-31+G*) calculations. The solvent effect was studied using the SCIPCM method. While the F , OH and NH 2 groups increase the stability of the trans-up conformation with respect to the trans-down conformation, [Formula: see text] appears to favor the trans-down conformation in an aqueous solution. Second, the triple helices of the tripeptide models, Ac – Pro – Pro(X) – Gly – H with the two proline residues in the down/down and down/up puckering conformations, were optimized with a repeating unit approach using the HF/6-31G* method. For the Ac – Pro – Pro – Gly – H model peptide, the calculated binding energies of the two triple helices with the different puckering modes are similar. All four substituents, F , OH , NH 2, and [Formula: see text], considerably increased the binding energy of the down/up helix, but only [Formula: see text] stabilizes the down/down triple helix. Our calculations indicate that the inter-chain electrostatic interactions involving the 4(R)-substituents play an important role in stabilizing triple helical collagen models and allow the rationalization of all available experimental observations. Further model studies indicate that the substituent effects by the F , OH and NH 2 substituents are local while the effect of [Formula: see text] is long-range in nature.