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A Virtual Reality Ensemble Molecular Dynamics Workflow to Study Complex Conformational Changes in Proteins

preprint
revised on 24.04.2020 and posted on 27.04.2020 by Jordi Juárez-Jiménez, Philip Tew, Michael o'connor, Salome Llabres, Rebecca Sage, David Glowacki, Julien Michel

Molecular dynamics (MD) simulations are increasingly used to elucidate relationships between protein structure, dynamics and their biological function. Currently it is extremely challenging to perform MD simulations of large-scale structural rearrangements in proteins that occur on millisecond timescales or beyond, as this requires very significant computational resources, or the use of cumbersome ‘collective variable’ enhanced sampling protocols. Here we describe a framework that combines ensemble MD simulations and virtual-reality visualization (eMD-VR) to enable users to interactively generate realistic descriptions of large amplitude, millisecond timescale protein conformational changes in proteins. Detailed tests demonstrate that eMD-VR substantially decreases the computational cost of folding simulations of a WW domain, without the need to define collective variables a priori. We further show that eMD-VR generated pathways can be combined with Markov State Models to describe the thermodynamics and kinetics of large-scale loop motions in the enzyme cyclophilin A. Our results suggest eMD-VR is a powerful tool for exploring protein energy landscapes in bioengineering efforts.

Funding

Horizon 2020 - ERC Proof of Concept 754654

EPSRC - EP/P011330/1

History

Email Address of Submitting Author

mail@julienmichel.net

Institution

University of Edinburgh

Country

United Kingdom

ORCID For Submitting Author

0000-0003-0360-1760

Declaration of Conflict of Interest

Philip Tew and Rebecca Sage are employees of the company Interactive Scientific that commercializes virtual-reality visualization software.

Version Notes

First version uploaded 11/02/2020

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