Hamiltonian Replica Exchange for Enhanced Sampling of the Conformational Landscape for Intrinsically Disordered Proteins

Abstract

Intrinsically disordered proteins (IDPs) are a class of proteins that lack a unique native three-dimensional structure. Molecular dynamics (MD) is an invaluable method to study the dynamics of folded proteins. However, there have been challenges in its application to simulating IDPs. One of these challenges is the need to sample a vast number of structural conformations. To help overcome this challenge, one of the methods that was introduced is the temperature replica exchange (TRE) algorithm. This method uses a random walk in temperature space to help overcome energy barriers. However, this method can require vast computing resources and the efficiency of the TRE algorithm is not well characterized. We use a variant of Hamiltonian replica exchange (HRE), which instead of temperature uses the scaling of the Lennard-Jones protein-water interactions. In conducting the algorithm in this manner, the computational requirements are reduced compared to TRE. Here, we used MD simulations on an IDP system to compare the sampling efficiency between these sampling algorithms. We tested this algorithm on the RS1 region of the serine/arginine-rich splicing factor 1; an IDP with many consecutive repeating RS residues. In on-going work, we are comparing the computational efficiency of the HRE algorithm to TRE, conventional MD simulation, as well as other HRE algorithms.