Exploring biomolecular dynamics and interactions using advanced sampling methods

Luitz, Manuel P.; Bomblies, Rainer; Ostermeir, Katja; Zacharias, Martin

doi:10.1088/0953-8984/27/32/323101

Cited by 30 publications

(28 citation statements)

References 150 publications

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“…Thanks to general advances in computer power, the development of dedicated hardware and advances in software and algorithms, atomistic molecular dynamics (MD) simulations are emerging as powerful approaches to characterize at the atomlevel protein dynamics on timescales from picosecond to microsecond and even milliseconds in few cases. 14,16,278,279 Coarse-grained descriptions, where the physical model to describe the protein and the environment is further simplified, may also be used to describe general patterns in protein dynamics, for example when combined with elastic network models. 280,281 Most other computational approaches classify…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

The Role of Protein Loops and Linkers in Conformational Dynamics and Allostery

et al. 2016

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Proteins are dynamic entities that undergo a plethora of conformational changes that may take place on a wide range of time scales. These changes can be as small as the rotation of one or a few side-chain dihedral angles or involve concerted motions in larger portions of the three-dimensional structure; both kinds of motions can be important for biological function and allostery. It is becoming increasingly evident that "connector regions" are important components of the dynamic personality of protein structures. These regions may be either disordered loops, i.e., poorly structured regions connecting secondary structural elements, or linkers that connect entire protein domains. Experimental and computational studies have, however, revealed that these regions are not mere connectors, and their role in allostery and conformational changes has been emerging in the last few decades. Here we provide a detailed overview of the structural properties and classification of loops and linkers, as well as a discussion of the main computational methods employed to investigate their function and dynamical properties. We also describe their importance for protein dynamics and allostery using as examples key proteins in cellular biology and human diseases such as kinases, ubiquitinating enzymes, and transcription factors.

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Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

The Role of Protein Loops and Linkers in Conformational Dynamics and Allostery

et al. 2016

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“…This PMF represents the free energy change associated with the dissociation or association of the partners along the RC. Sufficient sampling of relevant states within each umbrella window and overlap of sampled states between neighboring windows is of critical importance for convergence of the calculated free energy profile . Significant improvements can often be achieved by coupling Umbrella sampling with H‐REMD allowing exchanges of sampled states between separate U.S. windows .…”

Section: Rigorous Free Energy Approaches To Calculate Absolute Bindinmentioning

confidence: 99%

Computational prediction of protein–protein binding affinities

Siebenmorgen

Zacharias

2019

WIREs Comput Mol Sci

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133

128

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Protein–protein interactions form central elements of almost all cellular processes. Knowledge of the structure of protein–protein complexes but also of the binding affinity is of major importance to understand the biological function of protein–protein interactions. Even weak transient protein–protein interactions can be of functional relevance for the cell during signal transduction or regulation of metabolism. The structure of a growing number of protein–protein complexes has been solved in recent years. Combined with docking approaches or template‐based methods, it is possible to generate structural models of many putative protein–protein complexes or to design new protein–protein interactions. In order to evaluate the functional relevance of putative or predicted protein–protein complexes, realistic binding affinity prediction is of increasing importance. Several computational tools ranging from simple force‐field or knowledge‐based scoring of single protein–protein complexes to ensemble‐based approaches and rigorous binding free energy simulations are available to predict relative and absolute binding affinities of complexes. With a focus on molecular mechanics force‐field approaches the present review aims at presenting an overview on available methods and discussing advantages, approximations, and limitations of the various methods. This article is categorized under: Molecular and Statistical Mechanics > Molecular Interactions Molecular and Statistical Mechanics > Free Energy Methods Software > Molecular Modeling

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“…Conformational sampling of large biomolecules and other complex molecular systems is one of the key challenges in molecular dynamics (MD) simulations. [1][2][3][4] Even though conventional explicit solvent simulations have achieved microsecond to millisecond time scales in recent years, [5][6][7] enhanced sampling techniques that aim to observe rare dynamic events more frequently remain highly desirable in studies of many biological problems. [8][9][10][11][12][13][14][15] In particular, temperature-based replica exchange (T-RE) has been widely adopted as a powerful enhanced sampling technique for general biomolecular simulations.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of independence sampling in replica exchange simulations of ordered and disordered proteins

Lee

Chen²

2017

J Comput Chem

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Recasting temperature replica exchange (T-RE) as a special case of Gibbs sampling has led to a simple and efficient scheme for enhanced mixing (Chodera and Shirts, 2011). To critically examine if T-RE with independence sampling (T-REis) improves conformational sampling, we performed T-RE and T-REis simulations of ordered and disordered proteins using coarse-grained (CG) and atomistic models. The results demonstrate that T-REis effectively increase the replica mobility in temperatures space with minimal computational overhead, especially for folded proteins. However, enhanced mixing does not translate well into improved conformational sampling. The convergences of thermodynamic properties interested are similar, with slight improvements for T-REis of ordered systems. The study re-affirms the efficiency of T-RE does not appear to be limited by temperature diffusion, but by the inherent rates of spontaneous large-scale conformational re-arrangements. Due to its simplicity and efficacy of enhanced mixing, T-REis is expected to be more effective when incorporated with various Hamiltonian-RE protocols.

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Exploring biomolecular dynamics and interactions using advanced sampling methods

Cited by 30 publications

References 150 publications

The Role of Protein Loops and Linkers in Conformational Dynamics and Allostery

The Role of Protein Loops and Linkers in Conformational Dynamics and Allostery

Computational prediction of protein–protein binding affinities

Efficacy of independence sampling in replica exchange simulations of ordered and disordered proteins

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