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1
Krukenberg, Kristin A., Timothy O. Street, Laura A. Lavery, and David A. Agard. "Conformational dynamics of the molecular chaperone Hsp90." Quarterly Reviews of Biophysics 44, no. 2 (2011): 229–55. http://dx.doi.org/10.1017/s0033583510000314.
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AbstractThe ubiquitous molecular chaperone Hsp90 makes up 1–2% of cytosolic proteins and is required for viability in eukaryotes. Hsp90 affects the folding and activation of a wide variety of substrate proteins including many involved in signaling and regulatory processes. Some of these substrates are implicated in cancer and other diseases, making Hsp90 an attractive drug target. Structural analyses have shown that Hsp90 is a highly dynamic and flexible molecule that can adopt a wide variety of structurally distinct states. One driving force for these rearrangements is the intrinsic ATPase activity of Hsp90, as seen with other chaperones. However, unlike other chaperones, studies have shown that the ATPase cycle of Hsp90 is not conformationally deterministic. That is, rather than dictating the conformational state, ATP binding and hydrolysis only shift the equilibria between a pre-existing set of conformational states. For bacterial, yeast and human Hsp90, there is a conserved three-state (apo–ATP–ADP) conformational cycle; however; the equilibria between states are species specific. In eukaryotes, cytosolic co-chaperones regulate the in vivo dynamic behavior of Hsp90 by shifting conformational equilibria and affecting the kinetics of structural changes and ATP hydrolysis. In this review, we discuss the structural and biochemical studies leading to our current understanding of the conformational dynamics of Hsp90, as well as the roles that nucleotide, co-chaperones, post-translational modification and substrates play. This view of Hsp90's conformational dynamics was enabled by the use of multiple complementary structural methods including, crystallography, small-angle X-ray scattering (SAXS), electron microscopy, Förster resonance energy transfer (FRET) and NMR. Finally, we discuss the effects of Hsp90 inhibitors on conformation and the potential for developing small molecules that inhibit Hsp90 by disrupting the conformational dynamics.
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Ohno, Shiho, Noriyoshi Manabe, Jun Uzawa, and Yoshiki Yamaguchi. "Comparative Conformational Analysis of Acyclic Sugar Alcohols Ribitol, Xylitol and d-Arabitol by Solution NMR and Molecular Dynamics Simulations." Molecules 29, no. 5 (2024): 1072. http://dx.doi.org/10.3390/molecules29051072.
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Ribitol (C5H12O5) is an acyclic sugar alcohol that was recently identified in O-mannose glycan on mammalian α-dystroglycan. The conformation and dynamics of acyclic sugar alcohols such as ribitol are dependent on the stereochemistry of the hydroxyl groups; however, the dynamics are not fully understood. To gain insights into the conformation and dynamics of sugar alcohols, we carried out comparative analyses of ribitol, d-arabitol and xylitol by a crystal structure database search, solution NMR analysis and molecular dynamics (MD) simulations. The crystal structures of the sugar alcohols showed a limited number of conformations, suggesting that only certain stable conformations are prevalent among all possible conformations. The three-bond scholar coupling constants and exchange rates of hydroxyl protons were measured to obtain information on the backbone torsion angle and possible hydrogen bonding of each hydroxyl group. The 100 ns MD simulations indicate that the ribitol backbone has frequent conformational transitions with torsion angles between 180∘ and ±60∘, while d-arabitol and xylitol showed fewer conformational transitions. Taking our experimental and computational data together, it can be concluded that ribitol is more flexible than d-arabitol or xylitol, and the flexibility is at least in part defined by the configuration of the OH groups, which may form intramolecular hydrogen bonds.
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Garrido-Rodríguez, Pedro, Miguel Carmena-Bargueño, María Eugenia de la Morena-Barrio, et al. "Analysis of AlphaFold and molecular dynamics structure predictions of mutations in serpins." PLOS ONE 19, no. 7 (2024): e0304451. http://dx.doi.org/10.1371/journal.pone.0304451.
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Serine protease inhibitors (serpins) include thousands of structurally conserved proteins playing key roles in many organisms. Mutations affecting serpins may disturb their conformation, leading to inactive forms. Unfortunately, conformational consequences of serpin mutations are difficult to predict. In this study, we integrate experimental data of patients with mutations affecting one serpin with the predictions obtained by AlphaFold and molecular dynamics. Five SERPINC1 mutations causing antithrombin deficiency, the strongest congenital thrombophilia were selected from a cohort of 350 unrelated patients based on functional, biochemical, and crystallographic evidence supporting a folding defect. AlphaFold gave an accurate prediction for the wild-type structure. However, it also produced native structures for all variants, regardless of complexity or conformational consequences in vivo. Similarly, molecular dynamics of up to 1000 ns at temperatures causing conformational transitions did not show significant changes in the native structure of wild-type and variants. In conclusion, AlphaFold and molecular dynamics force predictions into the native conformation at conditions with experimental evidence supporting a conformational change to other structures. It is necessary to improve predictive strategies for serpins that consider the conformational sensitivity of these molecules.
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Li, Xin, Na Wang, Jinyue Yang, et al. "Molecular conformational evolution mechanism during nucleation of crystals in solution." IUCrJ 7, no. 3 (2020): 542–56. http://dx.doi.org/10.1107/s2052252520004959.
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Nucleation of crystals from solution is fundamental to many natural and industrial processes. In this work, the molecular mechanism of conformational polymorphism nucleation and the links between the molecular conformation in solutions and in crystals were investigated in detail by using 5-nitrofurazone as the model compound. Different polymorphs were prepared, and the conformations in solutions obtained by dissolving different polymorphs were analysed and compared. The solutions of 5-nitrofurazone were proven to contain multiple conformers through quantum chemical computation, Raman spectra analysis, 2D nuclear Overhauser effect spectroscopy spectra analysis and molecular dynamics simulation. The conformational evolution and desolvation path was illustrated according to the 1H NMR spectra of solutions with different concentrations. Finally, based on all the above analysis, the molecular conformational evolution path during nucleation of 5-nitrofurazone was illustrated. The results presented in this work shed a new light on the molecular mechanism of conformational polymorphism nucleation in solution.
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Agaeva, G., G. Safarli, and N. Godjaev. "MOLECULAR MODELLİNG OF CONFORMATİONAL FLEXİBİLİTY OF HYLAMBATİN MOLECULE." Russian Journal of Biological Physics and Chemisrty 7, no. 2 (2022): 194–98. http://dx.doi.org/10.29039/rusjbpc.2022.0502.
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The features of the spatial organization of the hylambatin molecule were investigated by methods of molecular mechanics and molecular dynamics. Hylambatin consists of twelve amino acid residues in the sequence: Asp-Pro-Pro-Asp-Pro-Asn-Arg-Phe-Tyr-Gly-Met-Met-NH2. Unlike all other tachykinins, hylambatin has a Met residue replacing the usual Leu at penultimate position. The tachykinin peptide hylambatin has been isolated and chemically characterized from methanol extracts of the skin of Hylambates maculatus, an African rhacophorid frog. It has been shown that intravenously administered hylambatin significantly increases the level of glucose and insulin in blood plasma. In this paper, the conformational flexibility of the hylambatin molecule was studied by methods of molecular mechanics and molecular dynamics. The conformational calculation of the peptide took into account non-valent and electrostatic interactions, hydrogen bonds and torsion potentials. Based on fragmentary analysis, stable spatial structures of the hylambatin dodecapeptide were determined, which can be represented as a set of conformations characterized by a relatively labile N-terminal tetrapeptide and a conformationally rigid C-terminal octapeptide. In the calculated stable conformational states, the effective interactions of the side chains of residues and hydrogen bonds were refined and energetically evaluated. It has been shown that the hylambatin molecule preferably forms practically isoenergetic conformations with various structural types at the N-end of the peptide chain, passing into the alpha helix at the C-end. By the method of molecular dynamics, the pattern of intramolecular mobility of stable conformations of the hylambatin molecule was modeled both in vacuum and surrounded by water molecules. Based on the calculated values of the dihedral angles, molecular models of energetically preferred conformational states of the hylambatin dodecapeptide were constructed.
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Tafi, A., Fabrizio Manetti, Federico Corelli, Stefano Alcaro, and Maurizio Botta. "Structural flexibility of hyaluronan oligomers as probed by molecular modelling." Pure and Applied Chemistry 75, no. 2-3 (2003): 359–66. http://dx.doi.org/10.1351/pac200375020359.
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In the last few years, molecular modeling studies have been published that are devoted to a better understanding of the structural flexibility of hyaluronan (HA). Further conformational investigations, however, are needed on this polysaccharide, such as the application of statistical methods to perform enhanced one-step conformational analyses of its subunits. Moreover, the adjustment of assisted model building and energy refinement (AMBER) force field could provide the appropriate computational tool to study the interactions of HA and its derivatives with proteins. The present paper reports a combined Monte Carlo (MC) and molecular dynamics (MD) approach applied to the conformational study of HA, using an adjusted version of AMBER force field and the generalized Born solvent-accessible surface area (GB/SA) continuum solvation model. The MC approach turned out to be extremely effective to outline a conformational survey of the disaccharides constituting HA. Complete sets of conformations of the monomers were provided for the first time, some of which had never been predicted. MD technique, integrating the MC results, correctly reproduced the unusual stiffness of HA and predicted the existence of a minor skew-boat conformation of the β-d-glucuronic moiety. The computational approach, as a whole, improved the comprehension of the dynamic behavior of HA and offered a clear causal explanation of the relative dynamics of the glycosidic linkages.
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Miller, Chad, Steven Schildcrout, Howard Mettee, and Ganesaratnam Balendiran. "Molecular dynamics of fibric acids." European Journal of Chemistry 13, no. 2 (2022): 186–95. http://dx.doi.org/10.5155/eurjchem.13.2.186-195.2275.
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1H- and 13C-NMR chemical shifts were measured for four fibric acids (bezafibrate, clofibric acid, fenofibric acid, and gemfibrozil), which are lipid-lowering drugs. Correlation is found with DFT-computed chemical shifts from the conformational analysis. Equilibrium populations of optimized conformers at 298 K are very different when based on computed Gibbs energies rather than on potential energies. This is due to the significant entropic advantages of extended rather than bent conformational shapes. Abundant conformers with intramolecular hydrogen bonding via five-member rings are computed for three fibric acids, but not gemfibrozil, which lacks suitable connectivity of carboxyl and phenoxy groups. Trends in computed atom-positional deviations, molecular volumes, surface areas, and dipole moments among the fibric acids and their constituent conformations indicate that bezafibrate has the greatest hydrophilicity and fenofibric acid has the greatest flexibility. Theoretical and experimental comparison of chemical shifts of standards with sufficient overlap of fragments containing common atoms, groups, and connectivity may provide a reliable minimal set to benchmark and generate leads.
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Andrałojć, Witold, Enrico Ravera, Loïc Salmon, Giacomo Parigi, Hashim M. Al-Hashimi, and Claudio Luchinat. "Inter-helical conformational preferences of HIV-1 TAR-RNA from maximum occurrence analysis of NMR data and molecular dynamics simulations." Physical Chemistry Chemical Physics 18, no. 8 (2016): 5743–52. http://dx.doi.org/10.1039/c5cp03993b.
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Spooner, Jacob, Heather Wiebe, Miranda Louwerse, Brandon Reader, and Noham Weinberg. "Theoretical analysis of high-pressure effects on conformational equilibria." Canadian Journal of Chemistry 96, no. 2 (2018): 178–89. http://dx.doi.org/10.1139/cjc-2017-0411.
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Along with temperature, pressure is the most important physical parameter determining the thermodynamic properties and reactivity of chemical systems. In this work, we discuss the effects of high pressure on conformational properties of organic molecules and propose an approach toward calculation of conformational volume changes based on molecular dynamics simulations. The results agree well with the experimental data. Furthermore, we demonstrate that pressure can be used as an instrument for fine-tuning of molecular conformations and to propel a properly constructed molecular rotor possessing a suitable combination of energy and volume profiles.
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Gaalswyk, Kari, and Christopher N. Rowley. "An explicit-solvent conformation search method using open software." PeerJ 4 (May 31, 2016): e2088. http://dx.doi.org/10.7717/peerj.2088.
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Computer modeling is a popular tool to identify the most-probable conformers of a molecule. Although the solvent can have a large effect on the stability of a conformation, many popular conformational search methods are only capable of describing molecules in the gas phase or with an implicit solvent model. We have developed a work-flow for performing a conformation search on explicitly-solvated molecules using open source software. This method uses replica exchange molecular dynamics (REMD) to sample the conformational states of the molecule efficiently. Cluster analysis is used to identify the most probable conformations from the simulated trajectory. This work-flow was tested on drug molecules α-amanitin and cabergoline to illustrate its capabilities and effectiveness. The preferred conformations of these molecules in gas phase, implicit solvent, and explicit solvent are significantly different.
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Ohno, Shiho, Noriyoshi Manabe, Takumi Yamaguchi, Jun Uzawa, and Yoshiki Yamaguchi. "Ribitol in Solution Is an Equilibrium of Asymmetric Conformations." Molecules 26, no. 18 (2021): 5471. http://dx.doi.org/10.3390/molecules26185471.
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Ribitol (C5H12O5), an acyclic sugar alcohol, is present on mammalian α-dystroglycan as a component of O-mannose glycan. In this study, we examine the conformation and dynamics of ribitol by database analysis, experiments, and computational methods. Database analysis reveals that the anti-conformation (180°) is populated at the C3–C4 dihedral angle, while the gauche conformation (±60°) is seen at the C2–C3 dihedral angle. Such conformational asymmetry was born out in a solid-state 13C-NMR spectrum of crystalline ribitol, where C1 and C5 signals are unequal. On the other hand, solution 13C-NMR has identical chemical shifts for C1 and C5. NMR 3J coupling constants and OH exchange rates suggest that ribitol is an equilibrium of conformations, under the influence of hydrogen bonds and/or steric hinderance. Molecular dynamics (MD) simulations allowed us to discuss such a chemically symmetric molecule, pinpointing the presence of asymmetric conformations evidenced by the presence of correlations between C2–C3 and C3–C4 dihedral angles. These findings provide a basis for understanding the dynamic structure of ribitol and the function of ribitol-binding enzymes.
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CHUMAN, Hiroshi. "Conformational analysis and molecular dynamics of peptides." Journal of Synthetic Organic Chemistry, Japan 45, no. 11 (1987): 1098–106. http://dx.doi.org/10.5059/yukigoseikyokaishi.45.1098.
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Ping, Jie, Pei Hao, Yi-Xue Li, and Jing-Fang Wang. "Molecular Dynamics Studies on the Conformational Transitions of Adenylate Kinase: A Computational Evidence for the Conformational Selection Mechanism." BioMed Research International 2013 (2013): 1–7. http://dx.doi.org/10.1155/2013/628536.
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Escherichia coliadenylate kinase (ADK) is a monomeric phosphotransferase enzyme that catalyzes reversible transfer of phosphoryl group from ATP to AMP with a large-scale domain motion. The detailed mechanism for this conformational transition remains unknown. In the current study, we performed long time-scale molecular dynamics simulations on both open and closed states of ADK. Based on the structural analyses of the simulation trajectories, we detected over 20 times conformational transitions between the open and closed states of ADK and identified two novel conformations as intermediate states in the catalytic processes. With these findings, we proposed a possible mechanism for the large-scale domain motion ofEscherichia coliADK and its catalytic process: (1) the substrate free ADK adopted an open conformation; (2) ATP bound with LID domain closure; (3) AMP bound with NMP domain closure; (4) phosphoryl transfer occurred with ATP, and AMP converted into two ADPs, and no conformational transition was detected in the enzyme; (5) LID domain opened with one ADP released; (6) another ADP released with NMP domain open. As both open and closed states sampled a wide range of conformation transitions, our simulation strongly supported the conformational selection mechanism forEscherichia coliADK.
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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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Wu, Shanshan, Tam T. T. N. Nguyen, Olga V. Moroz, et al. "Conformational heterogeneity of Savinase from NMR, HDX-MS and X-ray diffraction analysis." PeerJ 8 (June 26, 2020): e9408. http://dx.doi.org/10.7717/peerj.9408.
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Background Several examples have emerged of enzymes where slow conformational changes are of key importance for function and where low populated conformations in the resting enzyme resemble the conformations of intermediate states in the catalytic process. Previous work on the subtilisin protease, Savinase, from Bacillus lentus by NMR spectroscopy suggested that this enzyme undergoes slow conformational dynamics around the substrate binding site. However, the functional importance of such dynamics is unknown. Methods Here we have probed the conformational heterogeneity in Savinase by following the temperature dependent chemical shift changes. In addition, we have measured changes in the local stability of the enzyme when the inhibitor phenylmethylsulfonyl fluoride is bound using hydrogen-deuterium exchange mass spectrometry (HDX-MS). Finally, we have used X-ray crystallography to compare electron densities collected at cryogenic and ambient temperatures and searched for possible low populated alternative conformations in the crystals. Results The NMR temperature titration shows that Savinase is most flexible around the active site, but no distinct alternative states could be identified. The HDX shows that modification of Savinase with inhibitor has very little impact on the stability of hydrogen bonds and solvent accessibility of the backbone. The most pronounced structural heterogeneities detected in the diffraction data are limited to alternative side-chain rotamers and a short peptide segment that has an alternative main-chain conformation in the crystal at cryo conditions. Collectively, our data show that there is very little structural heterogeneity in the resting state of Savinase and hence that Savinase does not rely on conformational selection to drive the catalytic process.
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Ohhashi, Yumiko, Yoshiki Yamaguchi, Hiroshi Kurahashi, et al. "Molecular basis for diversification of yeast prion strain conformation." Proceedings of the National Academy of Sciences 115, no. 10 (2018): 2389–94. http://dx.doi.org/10.1073/pnas.1715483115.
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Self-propagating β-sheet–rich fibrillar protein aggregates, amyloid fibers, are often associated with cellular dysfunction and disease. Distinct amyloid conformations dictate different physiological consequences, such as cellular toxicity. However, the origin of the diversity of amyloid conformation remains unknown. Here, we suggest that altered conformational equilibrium in natively disordered monomeric proteins leads to the adaptation of alternate amyloid conformations that have different phenotypic effects. We performed a comprehensive high-resolution structural analysis of Sup35NM, an N-terminal fragment of the Sup35 yeast prion protein, and found that monomeric Sup35NM harbored latent local compact structures despite its overall disordered conformation. When the hidden local microstructures were relaxed by genetic mutations or solvent conditions, Sup35NM adopted a strikingly different amyloid conformation, which redirected chaperone-mediated fiber fragmentation and modulated prion strain phenotypes. Thus, dynamic conformational fluctuations in natively disordered monomeric proteins represent a posttranslational mechanism for diversification of aggregate structures and cellular phenotypes.
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AALTEN, Daan M. F. van, Bert L. de GROOT, Herman J. C. BERENDSEN, and John B. C. FINDLAY. "Conformational analysis of retinoids and restriction of their dynamics by retinoid-binding proteins." Biochemical Journal 319, no. 2 (1996): 543–50. http://dx.doi.org/10.1042/bj3190543.
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An exhaustive sampling of the configurational space of all-trans retinol using a 0.1 µs molecular-dynamics simulation is presented. The essential dynamics technique is used to describe the conformational changes in retinol using only three degrees of freedom. The different conformational states of retinol are analysed, and differences in free energy are calculated. The essential dynamics description allows a detailed comparison of free retinol and retinoids bound to retinoid-binding proteins and opens new possibilities in the small-molecule docking field. The dynamics of retinoids when complexed with their binding proteins are restricted, and they are forced into strained conformations. A ‘spring’ model for retinoid binding is proposed. This model is extended to a hypothesis for retinoid binding to visual pigments and bacteriorhodopsin.
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Samsonov, Sergey A., Stephan Theisgen, Thomas Riemer, Daniel Huster, and M. Teresa Pisabarro. "Glycosaminoglycan Monosaccharide Blocks Analysis by Quantum Mechanics, Molecular Dynamics, and Nuclear Magnetic Resonance." BioMed Research International 2014 (2014): 1–11. http://dx.doi.org/10.1155/2014/808071.
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Glycosaminoglycans (GAGs) play an important role in many biological processes in the extracellular matrix. In a theoretical approach, structures of monosaccharide building blocks of natural GAGs and their sulfated derivatives were optimized by a B3LYP6311ppdd//B3LYP/6-31+G(d) method. The dependence of the observed conformational properties on the applied methodology is described. NMR chemical shifts and proton-proton spin-spin coupling constants were calculated using the GIAO approach and analyzed in terms of the method's accuracy and sensitivity towards the influence of sulfation, O1-methylation, conformations of sugar ring, andωdihedral angle. The net sulfation of the monosaccharides was found to be correlated with the1H chemical shifts in the methyl group of the N-acetylated saccharides both theoretically and experimentally. Theωdihedral angle conformation populations of free monosaccharides and monosaccharide blocks within polymeric GAG molecules were calculated by a molecular dynamics approach using the GLYCAM06 force field and compared with the available NMR and quantum mechanical data. Qualitative trends for the impact of sulfation and ring conformation on the chemical shifts and proton-proton spin-spin coupling constants were obtained and discussed in terms of the potential and limitations of the computational methodology used to be complementary to NMR experiments and to assist in experimental data assignment.
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Balogh, Gábor, and Zsuzsanna Bereczky. "The Interaction of Factor Xa and IXa with Non-Activated Antithrombin in Michaelis Complex: Insights from Enhanced-Sampling Molecular Dynamics Simulations." Biomolecules 13, no. 5 (2023): 795. http://dx.doi.org/10.3390/biom13050795.
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The interaction between coagulation factors Xa and IXa and the activated state of their inhibitor, antithrombin (AT),have been investigated using X-ray diffraction studies. However, only mutagenesis data are available for non-activated AT. Our aim was to propose a model based on docking and advanced-sampling molecular dynamics simulations that can reveal the conformational behavior of the systems when AT is not binding a pentasaccharide. We built the initial structure for non-activated AT-FXa and AT-FIXa complexes using HADDOCK 2.4. The conformational behavior was studied using Gaussian accelerated molecular dynamics simulations. In addition to the docked complexes, two systems based on the X-ray structures were also simulated, with and without the ligand. The simulations revealed large variability in conformation for both factors. In the docking-based complex of AT-FIXa, conformations with stable Arg150–AT interactions can exist for longer time periods but the system also has a higher tendency for reaching states with very limited interaction with the “exosite” of AT. By comparing simulations with or without the pentasaccharide, we were able to gain insights into the effects of conformational activation on the Michaelis complexes. RMSF analysis and correlation calculations for the alpha-carbon atoms revealed important details of the allosteric mechanisms. Our simulations provide atomistic models for better understanding the conformational activation mechanism of AT against its target factors.
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IKEDA, Kazuyoshi, and Junichi HIGO. "Protein Conformational Analysis by Multicanonical Molecular Dynamics Simulation." Seibutsu Butsuri 43, no. 2 (2003): 64–69. http://dx.doi.org/10.2142/biophys.43.64.
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Ha, S. N., L. J. Madsen, and J. W. Brady. "Conformational analysis and molecular dynamics simulations of maltose." Biopolymers 27, no. 12 (1988): 1927–52. http://dx.doi.org/10.1002/bip.360271207.
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Queyroy, Séverine, Florian Müller-Plathe, and David Brown. "Molecular Dynamics Simulations of Cellulose Oligomers: Conformational Analysis." Macromolecular Theory and Simulations 13, no. 5 (2004): 427–40. http://dx.doi.org/10.1002/mats.200300054.
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Weber, Piotr, Piotr Bełdowski, Krzysztof Domino, Damian Ledziński, and Adam Gadomski. "Changes of Conformation in Albumin with Temperature by Molecular Dynamics Simulations." Entropy 22, no. 4 (2020): 405. http://dx.doi.org/10.3390/e22040405.
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This work presents the analysis of the conformation of albumin in the temperature range of 300 K – 312 K , i.e., in the physiological range. Using molecular dynamics simulations, we calculate values of the backbone and dihedral angles for this molecule. We analyze the global dynamic properties of albumin treated as a chain. In this range of temperature, we study parameters of the molecule and the conformational entropy derived from two angles that reflect global dynamics in the conformational space. A thorough rationalization, based on the scaling theory, for the subdiffusion Flory–De Gennes type exponent of 0 . 4 unfolds in conjunction with picking up the most appreciable fluctuations of the corresponding statistical-test parameter. These fluctuations coincide adequately with entropy fluctuations, namely the oscillations out of thermodynamic equilibrium. Using Fisher’s test, we investigate the conformational entropy over time and suggest its oscillatory properties in the corresponding time domain. Using the Kruscal–Wallis test, we also analyze differences between the mean root mean square displacement of a molecule at various temperatures. Here we show that its values in the range of 306 K – 309 K are different than in another temperature. Using the Kullback–Leibler theory, we investigate differences between the distribution of the mean root mean square displacement for each temperature and time window.
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Musavizadeh, Zahra, Alessandro Grottesi, Giulia Guarguaglini, and Alessandro Paiardini. "Phosphorylation, Mg-ADP, and Inhibitors Differentially Shape the Conformational Dynamics of the A-Loop of Aurora-A." Biomolecules 11, no. 4 (2021): 567. http://dx.doi.org/10.3390/biom11040567.
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The conformational state of the activation loop (A-loop) is pivotal for the activity of most protein kinases. Hence, the characterization of the conformational dynamics of the A-loop is important to increase our understanding of the molecular processes related to diseases and to support the discovery of small molecule kinase inhibitors. Here, we carry out a combination of molecular dynamics (MD) and essential dynamics (ED) analyses to fully map the effects of phosphorylation, ADP, and conformation disrupting (CD) inhibitors (i.e., CD532 and MLN8054) on the dynamics of the A-loop of Aurora-A. MD revealed that the stability of the A-loop in an open conformation is enhanced by single phospho-Thr-288, while paradoxically, the presence of a second phosphorylation at Thr-287 decreases such stability and renders the A-loop more fluctuant in time and space. Moreover, we found that this post-translational modification has a significant effect on the direction of the A-loop motions. ED analysis suggests that the presence of the phosphate moiety induces the dynamics of Aurora-A to sample two distinct energy minima, instead of a single large minimum, as in unphosphorylated Aurora-A states. This observation indicates that the conformational distributions of Aurora-A with both single and double phospho-threonine modifications are remarkably different from the unphosphorylated state. In the closed states, binding of CD532 and MLN8054 inhibitors has the effect of increasing the distance of the N- and C-lobes of the kinase domain of Aurora-A, and the angle analysis between those two lobes during MD simulations showed that the N- and C-lobes are kept more open in presence of CD532, compared to MLN8054. As the A-loop is a common feature of Aurora protein kinases, our studies provide a general description of the conformational dynamics of this structure upon phosphorylation and different ligands binding.
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Ramirez-Mondragon, Carlos A., Megin E. Nguyen, Jozafina Milicaj, et al. "Conserved Conformational Hierarchy across Functionally Divergent Glycosyltransferases of the GT-B Structural Superfamily as Determined from Microsecond Molecular Dynamics." International Journal of Molecular Sciences 22, no. 9 (2021): 4619. http://dx.doi.org/10.3390/ijms22094619.
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It has long been understood that some proteins undergo conformational transitions en route to the Michaelis Complex to allow chemistry. Examination of crystal structures of glycosyltransferase enzymes in the GT-B structural class reveals that the presence of ligand in the active site triggers an open-to-closed conformation transition, necessary for their catalytic functions. Herein, we describe microsecond molecular dynamics simulations of two distantly related glycosyltransferases that are part of the GT-B structural superfamily, HepI and GtfA. Simulations were performed using the open and closed conformations of these unbound proteins, respectively, and we sought to identify the major dynamical modes and communication networks that interconnect the open and closed structures. We provide the first reported evidence within the scope of our simulation parameters that the interconversion between open and closed conformations is a hierarchical multistep process which can be a conserved feature of enzymes of the same structural superfamily. Each of these motions involves of a collection of smaller molecular reorientations distributed across both domains, highlighting the complexities of protein dynamic involved in the interconversion process. Additionally, dynamic cross-correlation analysis was employed to explore the potential effect of distal residues on the catalytic efficiency of HepI. Multiple distal nonionizable residues of the C-terminal domain exhibit motions anticorrelated to positively charged residues in the active site in the N-terminal domain involved in substrate binding. Mutations of these residues resulted in a reduction in negatively correlated motions and an altered enzymatic efficiency that is dominated by lower Km values with kcat effectively unchanged. The findings suggest that residues with opposing conformational motions involved in the opening and closing of the bidomain HepI protein can allosterically alter the population and conformation of the “closed” state, essential to the formation of the Michaelis complex. The stabilization effects of these mutations likely equally influence the energetics of both the ground state and the transition state of the catalytic reaction, leading to the unaltered kcat. Our study provides new insights into the role of conformational dynamics in glycosyltransferase’s function and new modality to modulate enzymatic efficiency.
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Barth, Anders, Oleg Opanasyuk, Thomas-Otavio Peulen, et al. "Unraveling multi-state molecular dynamics in single-molecule FRET experiments. I. Theory of FRET-lines." Journal of Chemical Physics 156, no. 14 (2022): 141501. http://dx.doi.org/10.1063/5.0089134.
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Conformational dynamics of biomolecules are of fundamental importance for their function. Single-molecule studies of Förster Resonance Energy Transfer (smFRET) between a tethered donor and acceptor dye pair are a powerful tool to investigate the structure and dynamics of labeled molecules. However, capturing and quantifying conformational dynamics in intensity-based smFRET experiments remains challenging when the dynamics occur on the sub-millisecond timescale. The method of multiparameter fluorescence detection addresses this challenge by simultaneously registering fluorescence intensities and lifetimes of the donor and acceptor. Together, two FRET observables, the donor fluorescence lifetime τD and the intensity-based FRET efficiency E, inform on the width of the FRET efficiency distribution as a characteristic fingerprint for conformational dynamics. We present a general framework for analyzing dynamics that relates average fluorescence lifetimes and intensities in two-dimensional burst frequency histograms. We present parametric relations of these observables for interpreting the location of FRET populations in E–τ D diagrams, called FRET-lines. To facilitate the analysis of complex exchange equilibria, FRET-lines serve as reference curves for a graphical interpretation of experimental data to (i) identify conformational states, (ii) resolve their dynamic connectivity, (iii) compare different kinetic models, and (iv) infer polymer properties of unfolded or intrinsically disordered proteins. For a simplified graphical analysis of complex kinetic networks, we derive a moment-based representation of the experimental data that decouples the motion of the fluorescence labels from the conformational dynamics of the biomolecule. Importantly, FRET-lines facilitate exploring complex dynamic models via easily computed experimental observables. We provide extensive computational tools to facilitate applying FRET-lines.
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Valimehr, Sepideh, Rémi Vuillemot, Mohsen Kazemi, Slavica Jonic, and Isabelle Rouiller. "Analysis of the Conformational Landscape of the N-Domains of the AAA ATPase p97: Disentangling the Continuous Conformational Variability in Partially Symmetrical Complexes." International Journal of Molecular Sciences 25, no. 6 (2024): 3371. http://dx.doi.org/10.3390/ijms25063371.
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Single-particle cryo-electron microscopy (cryo-EM) has been shown to be effective in defining the structure of macromolecules, including protein complexes. Complexes adopt different conformations and compositions to perform their biological functions. In cryo-EM, the protein complexes are observed in solution, enabling the recording of images of the protein in multiple conformations. Various methods exist for capturing the conformational variability through analysis of cryo-EM data. Here, we analyzed the conformational variability in the hexameric AAA + ATPase p97, a complex with a six-fold rotational symmetric core surrounded by six flexible N-domains. We compared the performance of discrete classification methods with our recently developed method, MDSPACE, which uses 3D-to-2D flexible fitting of an atomic structure to images based on molecular dynamics (MD) simulations. Our analysis detected a novel conformation adopted by approximately 2% of the particles in the dataset and determined that the N-domains of p97 sway by up to 60° around a central position. This study demonstrates the application of MDSPACE in analyzing the continuous conformational changes in partially symmetrical protein complexes, systems notoriously difficult to analyze due to the alignment errors caused by their partial symmetry.
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Chen, Jianzhong, Jian Wang, Wanchun Yang, Lu Zhao, Juan Zhao, and Guodong Hu. "Molecular Mechanism of Phosphorylation-Mediated Impacts on the Conformation Dynamics of GTP-Bound KRAS Probed by GaMD Trajectory-Based Deep Learning." Molecules 29, no. 10 (2024): 2317. http://dx.doi.org/10.3390/molecules29102317.
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The phosphorylation of different sites produces a significant effect on the conformational dynamics of KRAS. Gaussian accelerated molecular dynamics (GaMD) simulations were combined with deep learning (DL) to explore the molecular mechanism of the phosphorylation-mediated effect on conformational dynamics of the GTP-bound KRAS. The DL finds that the switch domains are involved in obvious differences in conformation contacts and suggests that the switch domains play a key role in the function of KRAS. The analyses of free energy landscapes (FELs) reveal that the phosphorylation of pY32, pY64, and pY137 leads to more disordered states of the switch domains than the wild-type (WT) KRAS and induces conformational transformations between the closed and open states. The results from principal component analysis (PCA) indicate that principal motions PC1 and PC2 are responsible for the closed and open states of the phosphorylated KRAS. Interaction networks were analyzed and the results verify that the phosphorylation alters interactions of GTP and magnesium ion Mg2+ with the switch domains. It is concluded that the phosphorylation pY32, pY64, and pY137 tune the activity of KRAS through changing conformational dynamics and interactions of the switch domains. We anticipated that this work could provide theoretical aids for deeply understanding the function of KRAS.
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Dubovskii, Peter V., Kira M. Dubova, Gleb Bourenkov, et al. "Variability in the Spatial Structure of the Central Loop in Cobra Cytotoxins Revealed by X-ray Analysis and Molecular Modeling." Toxins 14, no. 2 (2022): 149. http://dx.doi.org/10.3390/toxins14020149.
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Cobra cytotoxins (CTs) belong to the three-fingered protein family and possess membrane activity. Here, we studied cytotoxin 13 from Naja naja cobra venom (CT13Nn). For the first time, a spatial model of CT13Nn with both “water” and “membrane” conformations of the central loop (loop-2) were determined by X-ray crystallography. The “water” conformation of the loop was frequently observed. It was similar to the structure of loop-2 of numerous CTs, determined by either NMR spectroscopy in aqueous solution, or the X-ray method. The “membrane” conformation is rare one and, to date has only been observed by NMR for a single cytotoxin 1 from N. oxiana (CT1No) in detergent micelle. Both CT13Nn and CT1No are S-type CTs. Membrane-binding of these CTs probably involves an additional step—the conformational transformation of the loop-2. To confirm this suggestion, we conducted molecular dynamics simulations of both CT1No and CT13Nn in the Highly Mimetic Membrane Model of palmitoiloleoylphosphatidylglycerol, starting with their “water” NMR models. We found that the both toxins transform their “water” conformation of loop-2 into the “membrane” one during the insertion process. This supports the hypothesis that the S-type CTs, unlike their P-type counterparts, require conformational adaptation of loop-2 during interaction with lipid membranes.
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Khan, Muhammad Naseem, Umar Farooq, Aneela Khushal, Tanveer A. Wani, Seema Zargar, and Sara Khan. "Unraveling potential EGFR kinase inhibitors: Computational screening, molecular dynamics insights, and MMPBSA analysis for targeted cancer therapy development." PLOS One 20, no. 5 (2025): e0321500. https://doi.org/10.1371/journal.pone.0321500.
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EGFR is critical for tumor angiogenesis and cancer progression, but existing treatments like erlotinib face limitations such as acquired resistance and side effects. To address these issues, this study employs structure-based drug design techniques including virtual screening, molecular docking, and molecular dynamics simulations to identify new small molecule inhibitors targeting the EGFR kinase domain. From an initial selection of 633,000 compounds from diverse databases, top candidates were identified based on their binding affinity and stability. The virtual screening and docking analyses revealed compounds with higher binding scores than erlotinib. Molecular dynamics simulations and Anisotropic Network Model (ANM) analysis uniquely report that EGFR undergoes significant conformational shifts: inward flap movements in the bound state stabilize a closed conformation, while outward movements in the free state result in a more open conformation. Among the identified inhibitors, compounds such as JFD00243, NPA015124, and others exhibited strong binding affinities and stable interactions with both active and inactive forms of EGFR. Notably, JFD00243 was effective in targeting EGFR in both active and inactive conformations. These findings suggest that the identified inhibitors could potentially overcome current treatment limitations and improve targeted cancer therapies by effectively inhibiting EGFR-mediated tumor angiogenesis.
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Sović, Karlo, Tea Ostojić, Ines Primožič, et al. "Conformational Analysis of Cinhonine and Cinhonidine by Tensor Decomposition of Molecular Dynamics Trajectories." Croatica chemica acta 92, no. 2 (2019): 259–67. http://dx.doi.org/10.5562/cca3557.
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Full conformational space of cinchonine and cinchonidine has been investigated by means of statistical analysis of quantum chemical molecular dynamics simulations. Recently developed procedure comprising principal component analysis of molecular dynamics trajectories was applied on cinchonine and cinchonidine as well as on their protonated and methylated quaternary derivatives. The method for full conformational analysis includes Cartesian coordinates sampling through quantum chemical molecular dynamics simulations, reduction of dimensionality by principal component analysis, determination of probability distributions in a reduced space of Cartesian coordinates and search for all the strict extrema points in probability distribution functions. In order to gain crucial insight in the understanding of chirality induction of these alkaloids, comparison of the determined conformational spaces of pseudo-enantiomers has been made. It was shown that protonation of the quinuclidine nitrogen atom stabilizes the conformers with the intramolecular 1N–H∙∙∙9O hydrogen bond whereas methylation on the same position results in the reduction of the domain of internal coordinates responsible for the conformational space.
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Bigman, Lavi S., and Yaakov Levy. "Conformational Analysis of Charged Homo-Polypeptides." Biomolecules 13, no. 2 (2023): 363. http://dx.doi.org/10.3390/biom13020363.
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Many proteins have intrinsically disordered regions (IDRs), which are often characterized by a high fraction of charged residues with polyampholytic (i.e., mixed charge) or polyelectrolytic (i.e., uniform charge) characteristics. Polyelectrolytic IDRs include consecutive positively charged Lys or Arg residues (K/R repeats) or consecutive negatively charged Asp or Glu residues (D/E repeats). In previous research, D/E repeats were found to be about five times longer than K/R repeats and to be much more common in eukaryotes. Within these repeats, a preference is often observed for E over D and for K over R. To understand the greater prevalence of D/E over K/R repeats and the higher abundance of E and K, we simulated the conformational ensemble of charged homo-polypeptides (polyK, polyR, polyD, and polyE) using molecular dynamics simulations. The conformational preferences and dynamics of these polyelectrolytic polypeptides change with changes in salt concentration. In particular, polyD and polyE are more sensitive to salt than polyK and polyR, as polyD and polyE tend to adsorb more divalent cations, which leads to their having more compact conformations. We conclude with a discussion of biophysical explanations for the relative abundance of charged amino acids and particularly for the greater abundance of D/E repeats over K/R repeats.
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Moore, Alexander F., David J. Newman, Shoba Ranganathan, and Fei Liu. "Imaginative Order from Reasonable Chaos: Conformation-Driven Activity and Reactivity in Exploring Protein–Ligand Interactions." Australian Journal of Chemistry 71, no. 12 (2018): 917. http://dx.doi.org/10.1071/ch18416.
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Sir Derek Barton’s seminal work on steroid conformational analysis opened up a new era of enquiry into how the preferred conformation of any molecule could have profound effects on its physical–chemical properties and activities. Conformation-based effects on molecular activity and reactivity continue to manifest, with one key area of investigation currently focussed on conformational entropy in driving protein–ligand interactions. Carrying on from Barton’s initial insight on natural product conformational properties, new questions now address how conformational flexibility within a bioactive natural product structural framework (reasonable chaos), can be directed to confer dynamically new protein–ligand interactions beyond the basic lock–key model (imaginative order). Here we summarise our work on exploring conformational diversity from fluorinated natural product fragments, and how this approach of conformation-coupled diversity-oriented synthesis can be used to iteratively derive ligands with enhanced specificity against highly homologous protein domains. Our results demonstrate that the conformation entropic states of highly conserved protein domains differ significantly, and this conformational diversity, beyond primary sequence analysis, can be duly captured and exploited by natural-product derived ligands with complementary conformational dynamics for enhancing recognition specificity in drug lead discovery.
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Agaeva, G. A., and G. Z. Najafova. "Conformational particularities of beta-amyloid peptide 25-35." Биофизика 68, no. 5 (2023): 871–77. http://dx.doi.org/10.31857/s0006302923050058.
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In Alzheimer's disease, beta-amyloid peptide (Ав) plays an important role in the mechanism of neurodegeneration. A small fragment of Лв(25-35) (with the sequence GSNKGAIIGLLM) is regarded to be the functional domain of Лв, responsible for its neurotoxic properties and represents the biological active region of Лв. Conformational analysis of each C-terminal segment of the peptide by the method of molecular mechanics revealed a limited number of most probable conformations and quite clearly helped to clarify what forces stabilize the structures. The obtained results showed that Лв(25-35) energetically has a propensity for adopting alpha-helix conformation of the C-terminal octapeptide segment. A molecular dynamics method was used to build a model of intramolecular mobility in the Лв(25-35) molecule. It was demonstrated that in low-energy conformations, Лв(25-35), the orientation of flexible structures of the N-terminal region with respect to the structures of the C-terminal region is different.
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McIntyre, Deane D., Markus W. Germann, and Hans J. Vogel. "Conformational analysis and complete assignment of the proton and carbon NMR spectra of ouabain and ouabagenin." Canadian Journal of Chemistry 68, no. 8 (1990): 1263–70. http://dx.doi.org/10.1139/v90-195.
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The 1H and 13C NMR spectra of the cardenolide ouabain and its aglycon ouabagenin have been completely assigned by two-dimensional NMR techniques, including phase-sensitive COSY and carbon–proton correlation (HETCOR, HMQC, and COLOC) spectra. The major conformer of these two compounds in solution is all-chair as determined from proton–proton coupling constants and is similar to that in the crystal lattice as previously determined by X-ray diffraction. The conformations of the A and D rings of ouabain in water are somewhat different than in DMSO/CDCl3 (2:1). At lower temperatures (−20 °C) signals from two conformers in slow exchange were readily observed in the 13C spectra, with an approximate ratio of 1:7. Molecular mechanics and dynamics calculations indicate that the conformational process responsible for this involves a chair/twist-boat interconversion of the A ring, with the all-chair conformer highly preferred. Keywords: ouabain, conformational analysis, 2-D NMR, molecular mechanics, molecular dynamics.
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Pandey, Bharati, Chetna Tyagi, Gopal Kumar Prajapati, et al. "Analysis of mutations of defensin protein using accelerated molecular dynamics simulations." PLOS ONE 15, no. 11 (2020): e0241679. http://dx.doi.org/10.1371/journal.pone.0241679.
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Plant defensins possess diverse biological functions that include antifungal and antibacterial activities and α-amylase and trypsin inhibitory properties. Two mutations, G9R and V39R, were confirmed to increase the antifungal activity of Raphanus sativus antifungal protein 2 (RsAFP2). Accelerated Molecular Dynamics (aMD) were carried out to examine the conformational changes present in these RsAFP2 mutants, and its two closest homologs compared to the wild-type protein. Specifically, the root mean square fluctuation values for the eight cysteine amino acids involved in the four disulfide bonds were low in the V39R mutant compared to the wild-type. Additionally, analysis of the free energy change revealed that G9R and V39R mutations exert a neutral and stabilizing effect on RsAFP2 conformation, and this is supported by the observed lower total energy of mutants compared to the wild-type, suggesting that enhanced stability of the mutants. However, MD simulations to a longer time scale would aid in capturing more conformational state of the wild-type and mutants defensin protein. Furthermore, the aMD simulations on fungal mimic membranes with RsAFP2 and its mutants and homologs showed that the mutant proteins caused higher deformation and water diffusion than the native RsAFP2, especially the V39R mutant. The mutant variants seem to interact by specifically targeting the POPC and POPI lipids amongst others. This work highlights the stabilizing effect of mutations at the 9th and 39th positions of RsAFP2 and their increased membrane deformation activity.
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Leitgeb, B., A. Szekeres, and G. Tóth. "Conformational analysis of endomorphin-1 by molecular dynamics methods." Journal of Peptide Research 62, no. 4 (2003): 145–57. http://dx.doi.org/10.1034/j.1399-3011.2003.00084.x.
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Leitgeb, Balázs, Ferenc Ötvös, and Géza Tóth. "Conformational analysis of endomorphin-2 by molecular dynamics methods." Biopolymers 68, no. 4 (2003): 497–511. http://dx.doi.org/10.1002/bip.10333.
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Dobrovolska, Olena, Øyvind Strømland, Ørjan Sele Handegård, et al. "Investigating the Disordered and Membrane-Active Peptide A-Cage-C Using Conformational Ensembles." Molecules 26, no. 12 (2021): 3607. http://dx.doi.org/10.3390/molecules26123607.
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The driving forces and conformational pathways leading to amphitropic protein-membrane binding and in some cases also to protein misfolding and aggregation is the subject of intensive research. In this study, a chimeric polypeptide, A-Cage-C, derived from α-Lactalbumin is investigated with the aim of elucidating conformational changes promoting interaction with bilayers. From previous studies, it is known that A-Cage-C causes membrane leakages associated with the sporadic formation of amorphous aggregates on solid-supported bilayers. Here we express and purify double-labelled A-Cage-C and prepare partially deuterated bicelles as a membrane mimicking system. We investigate A-Cage-C in the presence and absence of these bicelles at non-binding (pH 7.0) and binding (pH 4.5) conditions. Using in silico analyses, NMR, conformational clustering, and Molecular Dynamics, we provide tentative insights into the conformations of bound and unbound A-Cage-C. The conformation of each state is dynamic and samples a large amount of overlapping conformational space. We identify one of the clusters as likely representing the binding conformation and conclude tentatively that the unfolding around the central W23 segment and its reorientation may be necessary for full intercalation at binding conditions (pH 4.5). We also see evidence for an overall elongation of A-Cage-C in the presence of model bilayers.
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Belaidi, Salah, and Dalal Harkati. "Conformational Analysis in 18-Membered Macrolactones Based on Molecular Modeling." ISRN Organic Chemistry 2011 (April 19, 2011): 1–5. http://dx.doi.org/10.5402/2011/594242.
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Conformational analysis of 18-ring membered macrolactones has been carried out using molecular mechanics calculations and molecular dynamics. A high conformational flexibility of macrolactones was obtained, and an important stereoselectivity was observed for the complexed macrolides. For 18d macrolactone, which was presented by a most favored conformer with 20.1% without complex, it was populated with 50.1% in presence of Fe(CO)3.
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Ghoula, Mariem, Nathalie Janel, Anne-Claude Camproux, and Gautier Moroy. "Exploring the Structural Rearrangements of the Human Insulin-Degrading Enzyme through Molecular Dynamics Simulations." International Journal of Molecular Sciences 23, no. 3 (2022): 1746. http://dx.doi.org/10.3390/ijms23031746.
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Insulin-degrading enzyme (IDE) is a ubiquitously expressed metallopeptidase that degrades insulin and a large panel of amyloidogenic peptides. IDE is thought to be a potential therapeutic target for type-2 diabetes and neurodegenerative diseases, such as Alzheimer’s disease. IDE catalytic chamber, known as a crypt, is formed, so that peptides can be enclosed and degraded. However, the molecular mechanism of the IDE function and peptide recognition, as well as its conformation changes, remains elusive. Our study elucidates IDE structural changes and explains how IDE conformational dynamics is important to modulate the catalytic cycle of IDE. In this aim, a free-substrate IDE crystallographic structure (PDB ID: 2JG4) was used to model a complete structure of IDE. IDE stability and flexibility were studied through molecular dynamics (MD) simulations to witness IDE conformational dynamics switching from a closed to an open state. The description of IDE structural changes was achieved by analysis of the cavity and its expansion over time. Moreover, the quasi-harmonic analysis of the hinge connecting IDE domains and the angles formed over the simulations gave more insights into IDE shifts. Overall, our results could guide toward the use of different approaches to study IDE with different substrates and inhibitors, while taking into account the conformational states resolved in our study.
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Verma, Rajni, Jonathan M. Ellis, and Katie R. Mitchell-Koch. "Dynamic Preference for NADP/H Cofactor Binding/Release in E. coli YqhD Oxidoreductase." Molecules 26, no. 2 (2021): 270. http://dx.doi.org/10.3390/molecules26020270.
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YqhD, an E. coli alcohol/aldehyde oxidoreductase, is an enzyme able to produce valuable bio-renewable fuels and fine chemicals from a broad range of starting materials. Herein, we report the first computational solution-phase structure-dynamics analysis of YqhD, shedding light on the effect of oxidized and reduced NADP/H cofactor binding on the conformational dynamics of the biocatalyst using molecular dynamics (MD) simulations. The cofactor oxidation states mainly influence the interdomain cleft region conformations of the YqhD monomers, involved in intricate cofactor binding and release. The ensemble of NADPH-bound monomers has a narrower average interdomain space resulting in more hydrogen bonds and rigid cofactor binding. NADP-bound YqhD fluctuates between open and closed conformations, while it was observed that NADPH-bound YqhD had slower opening/closing dynamics of the cofactor-binding cleft. In the light of enzyme kinetics and structural data, simulation findings have led us to postulate that the frequently sampled open conformation of the cofactor binding cleft with NADP leads to the more facile release of NADP while increased closed conformation sampling during NADPH binding enhances cofactor binding affinity and the aldehyde reductase activity of the enzyme.
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Verma, Rajni, Jonathan M. Ellis, and Katie R. Mitchell-Koch. "Dynamic Preference for NADP/H Cofactor Binding/Release in E. coli YqhD Oxidoreductase." Molecules 26, no. 2 (2021): 270. http://dx.doi.org/10.3390/molecules26020270.
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YqhD, an E. coli alcohol/aldehyde oxidoreductase, is an enzyme able to produce valuable bio-renewable fuels and fine chemicals from a broad range of starting materials. Herein, we report the first computational solution-phase structure-dynamics analysis of YqhD, shedding light on the effect of oxidized and reduced NADP/H cofactor binding on the conformational dynamics of the biocatalyst using molecular dynamics (MD) simulations. The cofactor oxidation states mainly influence the interdomain cleft region conformations of the YqhD monomers, involved in intricate cofactor binding and release. The ensemble of NADPH-bound monomers has a narrower average interdomain space resulting in more hydrogen bonds and rigid cofactor binding. NADP-bound YqhD fluctuates between open and closed conformations, while it was observed that NADPH-bound YqhD had slower opening/closing dynamics of the cofactor-binding cleft. In the light of enzyme kinetics and structural data, simulation findings have led us to postulate that the frequently sampled open conformation of the cofactor binding cleft with NADP leads to the more facile release of NADP while increased closed conformation sampling during NADPH binding enhances cofactor binding affinity and the aldehyde reductase activity of the enzyme.
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Qu, Kun, Qiuluan Chen, Katarzyna A. Ciazynska, et al. "Engineered disulfide reveals structural dynamics of locked SARS-CoV-2 spike." PLOS Pathogens 18, no. 7 (2022): e1010583. http://dx.doi.org/10.1371/journal.ppat.1010583.
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The spike (S) protein of SARS-CoV-2 has been observed in three distinct pre-fusion conformations: locked, closed and open. Of these, the function of the locked conformation remains poorly understood. Here we engineered a SARS-CoV-2 S protein construct “S-R/x3” to arrest SARS-CoV-2 spikes in the locked conformation by a disulfide bond. Using this construct we determined high-resolution structures confirming that the x3 disulfide bond has the ability to stabilize the otherwise transient locked conformations. Structural analyses reveal that wild-type SARS-CoV-2 spike can adopt two distinct locked-1 and locked-2 conformations. For the D614G spike, based on which all variants of concern were evolved, only the locked-2 conformation was observed. Analysis of the structures suggests that rigidified domain D in the locked conformations interacts with the hinge to domain C and thereby restrains RBD movement. Structural change in domain D correlates with spike conformational change. We propose that the locked-1 and locked-2 conformations of S are present in the acidic high-lipid cellular compartments during virus assembly and egress. In this model, release of the virion into the neutral pH extracellular space would favour transition to the closed or open conformations. The dynamics of this transition can be altered by mutations that modulate domain D structure, as is the case for the D614G mutation, leading to changes in viral fitness. The S-R/x3 construct provides a tool for the further structural and functional characterization of the locked conformations of S, as well as how sequence changes might alter S assembly and regulation of receptor binding domain dynamics.
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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 (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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Lin, Shawn H., Dacheng Zhao, Vivian Deng, et al. "Integration Host Factor Binds DNA Holliday Junctions." International Journal of Molecular Sciences 24, no. 1 (2022): 580. http://dx.doi.org/10.3390/ijms24010580.
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Integration host factor (IHF) is a nucleoid-associated protein involved in DNA packaging, integration of viral DNA and recombination. IHF binds with nanomolar affinity to duplex DNA containing a 13 bp consensus sequence, inducing a bend of ~160° upon binding. We determined that IHF binds to DNA Four-way or Holliday junctions (HJ) with high affinity regardless of the presence of the consensus sequence, signifying a structure-based mechanism of recognition. Junctions, important intermediates in DNA repair and homologous recombination, are dynamic and can adopt either an open or stacked conformation, where the open conformation facilitates branch migration and strand exchange. Using ensemble and single molecule Förster resonance energy transfer (FRET) methods, we investigated IHF-induced changes in the population distribution of junction conformations and determined that IHF binding shifts the population to the open conformation. Further analysis of smFRET dynamics revealed that even in the presence of protein, the junctions remain dynamic as fast transitions are observed for the protein-bound open state. Protein binding alters junction conformational dynamics, as cross correlation analyses reveal the protein slows the transition rate at 1 mM Mg2+ but accelerates the transition rate at 10 mM Mg2+. Stopped flow kinetic experiments provide evidence for two binding steps, a rapid, initial binding step followed by a slower step potentially associated with a conformational change. These measurements also confirm that the protein remains bound to the junction during the conformer transitions and further suggest that the protein forms a partially dissociated state that allows junction arms to be dynamic. These findings, which demonstrate that IHF binds HJs with high affinity and stabilizes junctions in the open conformation, suggest that IHF may play multiple roles in the processes of integration and recombination in addition to stabilizing bacterial biofilms.
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Wang, Xuebin, Ning Liu, Nuan Li, Shaoyong Lu, and Zongtao Chai. "Mechanistic Insights into the Mechanism of Allosteric Inhibition of Ubiquitin-Specific Protease 7 (USP7)." Biomolecules 15, no. 6 (2025): 749. https://doi.org/10.3390/biom15060749.
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Ubiquitin-specific protease 7 (USP7), a deubiquitinase enzyme responsible for removing ubiquitin (Ub) from target proteins, plays a crucial role in oncogenic pathways and has been implicated in various human diseases. X-ray crystallography has revealed distinct conformations of USP7, including apo (ligand-free), allosteric inhibitor-, and Ub-bound states. However, the dynamic mechanisms underlying the allosteric inhibition of USP7 remain unclear. This study investigates the effect of allosteric inhibitor binding on the dynamics of USP7 through multiple replica molecular dynamics simulations. Our results demonstrate that Ub binding stabilizes the USP7 conformation, while allosteric inhibitor binding increases flexibility and variability in the fingers and palm domains of USP7. Furthermore, our analysis of USP7 local regions reveals that allosteric inhibitor binding not only restrains the dynamics of the C-terminal Ub binding site, thereby impeding the accessibility of Ub to USP7, but also disrupts the proper alignment of the catalytic triad (Cys223-His464-Asp481) in USP7. Additionally, community network analysis indicates that intra-domain communications within the fingers domain in USP7 are significantly enhanced upon allosteric inhibitor binding. This study reveals that the binding of an allosteric inhibitor induces a dynamic shift in enzyme’s conformational equilibrium, effectively disrupting its catalytic activity through allosteric modulation.
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Salvino, Joseph M., Peter R. Seoane, and Roland E. Dolle. "Conformational analysis of bradykinin by annealed molecular dynamics and comparison to NMR-derived conformations." Journal of Computational Chemistry 14, no. 4 (1993): 438–44. http://dx.doi.org/10.1002/jcc.540140407.
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Olivos-Ramirez, Gustavo E., Luis F. Cofas-Vargas, Tobias Madl, and Adolfo B. Poma. "Conformational and Stability Analysis of SARS-CoV-2 Spike Protein Variants by Molecular Simulation." Pathogens 14, no. 3 (2025): 274. https://doi.org/10.3390/pathogens14030274.
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We performed a comprehensive structural analysis of the conformational space of several spike (S) protein variants using molecular dynamics (MD) simulations. Specifically, we examined four well-known variants (Delta, BA.1, XBB.1.5, and JN.1) alongside the wild-type (WT) form of SARS-CoV-2. The conformational states of each variant were characterized by analyzing their distributions within a selected space of collective variables (CVs), such as inter-domain distances between the receptor-binding domain (RBD) and the N-terminal domain (NTD). Our primary focus was to identify conformational states relevant to potential structural transitions and to determine the set of native contacts (NCs) that stabilize these conformations. The results reveal that genetically more distant variants, such as XBB.1.5, BA.1, and JN.1, tend to adopt more compact conformational states compared to the WT. Additionally, these variants exhibit novel NC profiles, characterized by an increased number of specific contacts distributed among ionic, polar, and nonpolar residues. We further analyzed the impact of specific mutations, including T478K, N500Y, and Y504H. These mutations not only enhance interactions with the human host receptor but also alter inter-chain stability by introducing additional NCs compared to the WT. Consequently, these mutations may influence the accessibility of certain protein regions to neutralizing antibodies. Overall, these findings contribute to a deeper understanding of the structural and functional variations among S protein variants.
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Stepanenko, Darya, Yuzhang Wang, and Carlos Simmerling. "Assessing pH-Dependent Conformational Changes in the Fusion Peptide Proximal Region of the SARS-CoV-2 Spike Glycoprotein." Viruses 16, no. 7 (2024): 1066. http://dx.doi.org/10.3390/v16071066.
Full textAbstract:
One of the entry mechanisms of the SARS-CoV-2 coronavirus into host cells involves endosomal acidification. It has been proposed that under acidic conditions, the fusion peptide proximal region (FPPR) of the SARS-CoV-2 spike glycoprotein acts as a pH-dependent switch, modulating immune response accessibility by influencing the positioning of the receptor binding domain (RBD). This would provide indirect coupling of RBD opening to the environmental pH. Here, we explored this possible pH-dependent conformational equilibrium of the FPPR within the SARS-CoV-2 spike glycoprotein. We analyzed hundreds of experimentally determined spike structures from the Protein Data Bank and carried out pH-replica exchange molecular dynamics to explore the extent to which the FPPR conformation depends on pH and the positioning of the RBD. A meta-analysis of experimental structures identified alternate conformations of the FPPR among structures in which this flexible regions was resolved. However, the results did not support a correlation between the FPPR conformation and either RBD position or the reported pH of the cryo-EM experiment. We calculated pKa values for titratable side chains in the FPPR region using PDB structures, but these pKa values showed large differences between alternate PDB structures that otherwise adopt the same FPPR conformation type. This hampers the comparison of pKa values in different FPPR conformations to rationalize a pH-dependent conformational change. We supplemented these PDB-based analyses with all-atom simulations and used constant-pH replica exchange molecular dynamics to estimate pKa values in the context of flexibility and explicit water. The resulting titration curves show good reproducibility between simulations, but they also suggest that the titration curves of the different FPPR conformations are the same within the error bars. In summary, we were unable to find evidence supporting the previously published hypothesis of an FPPR pH-dependent equilibrium: neither from existing experimental data nor from constant-pH MD simulations. The study underscores the complexity of the spike system and opens avenues for further exploration into the interplay between pH and SARS-CoV-2 viral entry mechanisms.