Exploration of conformational transition pathways from coarse-grained simulations

Sfriso, Pedro; Hospital, Adam; Emperador, Agustí; Orozco, Modesto

doi:10.1093/bioinformatics/btt324

Cited by 29 publications

(35 citation statements)

References 71 publications

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“…Thus, we conducted a MD study to explore the dynamical properties of hCD81 LEL in its monomeric state compared with previous studies (Harman et al, 2015;Kong et al, 2013;Drummer et al, 2002). For the selection of the best initial models out of the 15 solved X-ray structures for an atomistic MD study, an exploratory coarse-grained simulation was performed (Sfriso et al, 2013). This protocol identified molecules 2, 8, 12, 13, and 14 as representative class structures (Figure 2A).…”

Section: Microsecond-timescale Molecular Dynamicsmentioning

confidence: 99%

Mechanism of Structural Tuning of the Hepatitis C Virus Human Cellular Receptor CD81 Large Extracellular Loop

et al. 2017

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Hepatitis C virus (HCV) enters into human hepatocytes via tetraspanin hCD81. HCV glycoprotein E2 recognizes the "head" subdomain of the large extracellular loop (LEL) of CD81 (hCD81), but the precise mechanism of virus cell attachment and entry remains elusive. Here, by combining the structural analysis of a conspicuous number of crystallized CD81 molecules with molecular dynamics simulations, we show that the conformational plasticity of the hCD81 head subdomain is a molecular property of the receptor. The observed closed, intermediate, and open conformations of the head subdomain provide distinct binding platforms. Simulations at pH 7.4 and 4.0 indicate that this dynamism is pH modulated. The crystallized double conformation of the disulfide bridge C157-C175 at the base of the head subdomain identifies this bond as the molecular zipper of the plasticity of hCD81. We propose that this conformational dependence of hCD81, which is finely tuned by pH and redox conditions, enables the virus-receptor interactions to diversely re-engage at endosomal conditions.

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Section: Microsecond-timescale Molecular Dynamicsmentioning

confidence: 99%

Mechanism of Structural Tuning of the Hepatitis C Virus Human Cellular Receptor CD81 Large Extracellular Loop

et al. 2017

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“…DMD allows for increased sampling with fewer computational resources, which is imperative in dynamics studies where multiple replicates of long trajectories are necessary for statistically distinguishing thermodynamic fluctuations from meaningful rearrangements in structure. For example, Sfriso et al [19] implemented coarse-grained DMD simulations to map protein conformational transitions. By taking advantage of the increased sampling of conformational space made possible by DMD event search algorithms [3–5], the authors create a tool that can trace complex, non-linear transitions in agreement with experiment without distortions in protein structure.…”

Section: Protein Dynamics and Functionmentioning

confidence: 99%

Applications of Discrete Molecular Dynamics in biology and medicine

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Dokholyan

2016

Current Opinion in Structural Biology

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Discrete Molecular Dynamics (DMD) is a physics-based simulation method using discrete energetic potentials rather than traditional continuous potentials, allowing microsecond time scale simulations of biomolecular systems to be performed on personal computers rather than supercomputers or specialized hardware. With the ongoing explosion in processing power even in personal computers, applications of DMD have similarly multiplied. In the past two years, researchers have used DMD to model structures of disease-implicated protein folding intermediates, study assembly of protein complexes, predict protein-protein binding conformations, engineer rescue mutations in disease-causative protein mutants, design a protein conformational switch to control cell signaling, and describe the behavior of polymeric dispersants for environmental cleanup of oil spills, among other innovative applications.

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“…Being limited to an equilibrium basin, pathway generation requires iterative computation and deformation along selected NMs, which can produce stereochemical distortions. Although these issues can be reduced applying internal coordinates20, structure corrections41, or just using the modes to bias more realistic simulations4243, mode selection still poses a problem. Here the use of the network potential in the context of a BD simulation avoids unrealistic structure deformations and provides spontaneous sampling along the relevant modes.…”

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Prediction and validation of protein intermediate states from structurally rich ensembles and coarse-grained simulations

et al. 2016

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Protein conformational changes are at the heart of cell functions, from signalling to ion transport. However, the transient nature of the intermediates along transition pathways hampers their experimental detection, making the underlying mechanisms elusive. Here we retrieve dynamic information on the actual transition routes from principal component analysis (PCA) of structurally-rich ensembles and, in combination with coarse-grained simulations, explore the conformational landscapes of five well-studied proteins. Modelling them as elastic networks in a hybrid elastic-network Brownian dynamics simulation (eBDIMS), we generate trajectories connecting stable end-states that spontaneously sample the crystallographic motions, predicting the structures of known intermediates along the paths. We also show that the explored non-linear routes can delimit the lowest energy passages between end-states sampled by atomistic molecular dynamics. The integrative methodology presented here provides a powerful framework to extract and expand dynamic pathway information from the Protein Data Bank, as well as to validate sampling methods in general.

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Exploration of conformational transition pathways from coarse-grained simulations

Abstract: Freely available on the web at http://mmb.irbbarcelona.org/GOdMD.

Cited by 29 publications

References 71 publications

Mechanism of Structural Tuning of the Hepatitis C Virus Human Cellular Receptor CD81 Large Extracellular Loop

Mechanism of Structural Tuning of the Hepatitis C Virus Human Cellular Receptor CD81 Large Extracellular Loop

Applications of Discrete Molecular Dynamics in biology and medicine

Prediction and validation of protein intermediate states from structurally rich ensembles and coarse-grained simulations

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