A study of intrinsically disordered proteins using molecular dynamics simulations

Abstract

Over the last decades, molecular dynamics simulations have been successfully applied to relevant biological problems such as protein-ligand, protein-protein binding as well as protein folding. A perfect challenge for molecular simulations is the study of intrinsically disordered proteins as they present faster timescales than structured proteins, which can be explored more exhaustively. The main objectives of this work are the exploration of the conformational space of p53 by revealing the presence of many partially ordered states, the reconstruction of the coupled folding and binding of a disordered protein and its folded partner by applying novel reinforcement learning inspired sampling algorithms, and the performance of free-ligand binding assays in order to address the potential druggability of disordered proteins. The compendium of work presented here contributes to the understanding of such intrinsically disordered proteins at an atomistic level, highlighting key aspects of their behavior in isolation, binding mechanisms, and external modulation.