Enhanced sampling techniques in biomolecular simulations

Spiwok, Vojtěch; Šućur, Zoran; Hošek, Petr

doi:10.1016/j.biotechadv.2014.11.011

Cited by 100 publications

(81 citation statements)

References 83 publications

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“…4), as well as for other systems (27). In some applications, MDeNM was shown to perform better than other well-established enhanced sampling methods such as metadynamics or umbrella sampling (27,(41)(42)(43)(44)(45)(46).…”

Section: Discussionmentioning

confidence: 97%

Conformational Equilibrium of CDK/Cyclin Complexes by Molecular Dynamics with Excited Normal Modes

Floquet

Costa

Batista

et al. 2015

Biophysical Journal

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Cyclin-dependent kinases (CDKs) and their associated regulatory cyclins are central for timely regulation of cell-cycle progression. They constitute attractive pharmacological targets for development of anticancer therapeutics, since they are frequently deregulated in human cancers and contribute to sustained, uncontrolled tumor proliferation. Characterization of their structural/dynamic features is essential to gain in-depth insight into structure-activity relationships. In addition, the identification of druggable pockets or key intermediate conformations yields potential targets for the development of novel classes of inhibitors. Structural studies of CDK2/cyclin A have provided a wealth of information concerning monomeric/heterodimeric forms of this kinase. There is, however, much less structural information for other CDK/cyclin complexes, including CDK4/cyclin D1, which displays an alternative (open) position of the cyclin partner relative to CDK, contrasting with the closed CDK2/cyclin A conformation. In this study, we carried out normal-mode analysis and enhanced sampling simulations with our recently developed method, molecular dynamics with excited normal modes, to understand the conformational equilibrium on these complexes. Interestingly, the lowest-frequency normal mode computed for each complex described the transition between the open and closed conformations. Exploration of these motions with an explicit-solvent representation using molecular dynamics with excited normal modes confirmed that the closed conformation is the most stable for the CDK2/cyclin A complex, in agreement with their experimentally available structures. On the other hand, we clearly show that an open↔closed equilibrium may exist in CDK4/cyclin D1, with closed conformations resembling that captured for CDK2/cyclin A. Such conformational preferences may result from the distinct distributions of frustrated contacts in each complex. Using the same approach, the putative roles of the Thr(160) phosphoryl group and the T-loop conformation were investigated. These results provide a dynamic view of CDKs revealing intermediate conformations not yet characterized for CDK members other than CDK2, which will be useful for the design of inhibitors targeting critical conformational transitions.

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Section: Discussionmentioning

confidence: 97%

Conformational Equilibrium of CDK/Cyclin Complexes by Molecular Dynamics with Excited Normal Modes

Floquet

Costa

Batista

et al. 2015

Biophysical Journal

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“…Path CVs and property map CVs are evaluated using Equation (1). The distance between the current structure x and landmark structure a i , D(x, a i ), is computed in every step.…”

Section: Floating Close Structurementioning

confidence: 99%

“…1 One family of methods uses a bias potential or bias force acting in directions of one or few predefined degrees of freedom, also referred to as collective variables (CVs). The idea behind these methods is to enhance the sampling of CVs in order to facilitate a conformational change, intermolecular interaction, chemical reaction, or other simulated processes.…”

Section: Introductionmentioning

confidence: 99%

Reducing the number of mean-square deviation calculations with floating close structure in metadynamics

Pazúriková

Křenek

Spiwok

et al. 2017

The Journal of Chemical Physics

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Metadynamics is an important collective-coordinate-based enhanced sampling simulation method. Its performance depends significantly on the capability of collective coordinates to describe the studied molecular processes. Collective coordinates based on comparison with reference landmark structures can be used to enhance sampling in highly complex systems; however, they may slow down simulations due to high number of structure-structure distance (e.g., mean-square deviation) calculations. Here we introduce an approximation of root-mean-square or mean-square deviation that significantly reduces numbers of computationally expensive operations. We evaluate its accuracy and theoretical performance gain with metadynamics simulations on two molecular systems.

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“…Free‐energy calculations based on enhanced‐sampling (ES) molecular dynamics (MD) simulations play an increasingly important role in biochemistry and structural biology . These methods provide a quantitative framework grounded on statistical thermodynamics through which conformational mechanisms and chemical reactions can be examined and characterized, transcending the often‐anecdotal insights attainable through conventional simulations.…”

Section: Introductionmentioning

confidence: 99%

Atomic‐resolution dissection of the energetics and mechanism of isomerization of hydrated ATP‐Mg²⁺ through the SOMA string method

2015

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The atomic mechanisms of isomerization of ATP-Mg(2+) in solution are characterized using the recently developed String Method with Optimal Molecular Alignment (SOMA) and molecular-dynamics simulations. Bias-Exchange Metadynamics simulations are first performed to identify the primary conformers of the ATP-Mg(2+) complex and their connectivity. SOMA is then used to elucidate the minimum free-energy path (MFEP) for each transition, in a 48-dimensional space. Analysis of the per-atom contributions to the global free-energy profiles reveals that the mechanism of these transitions is controlled by the Mg(2+) ion and its coordinating oxygen atoms in the triphosphate moiety, as well as by the ion-hydration shell. Metadynamics simulations in path collective variables based on the MFEP demonstrate these isomerizations proceed across a narrow channel of configurational space, thus validating the premise underlying SOMA. This study provides a roadmap for the examination of conformational changes in biomolecules, based on complementary enhanced-sampling techniques with different strengths. © 2015 Wiley Periodicals, Inc.

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Enhanced sampling techniques in biomolecular simulations

Cited by 100 publications

References 83 publications

Conformational Equilibrium of CDK/Cyclin Complexes by Molecular Dynamics with Excited Normal Modes

Conformational Equilibrium of CDK/Cyclin Complexes by Molecular Dynamics with Excited Normal Modes

Reducing the number of mean-square deviation calculations with floating close structure in metadynamics

Atomic‐resolution dissection of the energetics and mechanism of isomerization of hydrated ATP‐Mg²⁺ through the SOMA string method

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Enhanced sampling techniques in biomolecular simulations

Cited by 100 publications

References 83 publications

Conformational Equilibrium of CDK/Cyclin Complexes by Molecular Dynamics with Excited Normal Modes

Conformational Equilibrium of CDK/Cyclin Complexes by Molecular Dynamics with Excited Normal Modes

Reducing the number of mean-square deviation calculations with floating close structure in metadynamics

Atomic‐resolution dissection of the energetics and mechanism of isomerization of hydrated ATP‐Mg2+ through the SOMA string method

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Atomic‐resolution dissection of the energetics and mechanism of isomerization of hydrated ATP‐Mg²⁺ through the SOMA string method