Molecular Simulations of Intrinsically Disordered Proteins and Their Binding Mechanisms

Intrinsically disordered proteins (IDPs) lack well-defined secondary or tertiary structures in solution but are found to be involved in a wide range of critical cellular processes that highlight their functional importance. IDPs usually undergo folding upon binding to their targets. Such binding coupled to folding behavior has widened our perspective on the protein structure-dynamics-function paradigm in molecular biology. However, characterizing the folding upon binding mechanism of IDPs experimentally remains quite challenging. Molecular simulations emerge as a potentially powerful tool that offers information complementary to experiments. Here we present a general computational framework for the molecular simulations of IDP folding upon binding processes that combines all-atom molecular dynamics (MD) and coarse-grained simulations. The classical all-atom molecular dynamics approach using GPU acceleration allows the researcher to explore the properties of the IDP conformational ensemble, whereas coarse-grained structure-based models implemented with parameters carefully calibrated to available experimental measurements can be used to simulate the entire folding upon binding process. We also discuss a set of tools for the analysis of MD trajectories and describe the details of the computational protocol to follow so that it can be adapted by the user to study any IDP in isolation and in complex with partners.