Many proteins are highly dynamic molecules and in recent years there has been a growing trend towards Ensemble-Based Drug Design (EBDD) workflows that incorporate information about protein motions in the drug design process by describing a protein as a structural ensemble. Molecular dynamics (MD) simulations are an important component of EBDD workflows to generate such protein structural ensembles because few experimental methodologies can currently describe with atomistic resolution protein motions. To date there is no easy way for humans to interact efficiently with representations of structural ensembles because existing software interfaces were originally designed to visualize static structures. The major challenge is that any user interface for EBDD must translate the high spatial (thousands of atoms) and temporal (dynamic motions over pico to millisecond timescales) complexity of molecular motions into intuitive representations that humans can easily interact with.<br/>In collaboration with the company Interactive Scientific and the University of Bristol we have developed a proof of concept Virtual Reality based user interface (VRUI) that enables users to effortlessly setup and submit MD simulations to generate protein structural ensembles (Figure 1). Users may define interactively biasing potentials to steer the MD simulations towards regions of conformational space they deem relevant. A trajectory manager interface enables users to keep track of the various simulations performed during a project. We have used our prototype to explore molecular motions of different complexity on a set of proteins. We have also demonstrated the ability of the VRUI prototype to generate realistic conformational changes in protein structures against established enhanced sampling methodologies, and to provide scientifically valid input for Markov State modelling workflows.

Development of a virtual reality interface for molecular simulations-driven interactive ensemble-based drug design

2019 Fall National Meeting

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