Combining Molecular Dynamics and Biopolymer Docking

Presentation given at  2nd Workshop on High-Throughput Molecular Dynamics 2015 at the Barcelona biomedical research park 

Abstract:

High-throughput docking is most reliable when no structural change occurs in the receptor (i.e., rigid docking). However, in vivo (and in vitro) ligand binding and protein-protein interactions usually result in conformational change. To determine if we can overcome the limits of current docking software, we have performed ensemble docking runs, gathering sets of receptor and ligand conformations from microsecond-timescale all-atom molecular dynamics simulations. Here we provide insights and guidelines for others who plan to do likewise. As a case study, we present results from ensemble docking of a therapeutic polymer of FdUMP (5-fluoro-2′-deoxyuridine-5′-O-monophosphate) – a topoisomerase-1 (Top1), apoptosis-inducing poison – to Albumin and Vitronectin, showing that partially folded states of the FdUMP strand have the lowest free energy of binding to both proteins. We also present an example of this method applied to protein-protein interactions with two nucleotide binding proteins from Bacillus subtilis along with their interactions with ATP in complex. From these latter investigations, we predict a 3D structure in good agreement with results from residue mutation experiments. Finally, we propose a methodology for visualizing the uncertainty in these data – a method that can be applied to computational biology results in general.