MD Simulation Trajectories of Multiple Intrinsically Disordered Proteins Reveal Order to Disorder Transitions that Bear Functional Significance

Abstract

Intrinsically disordered proteins (IDPs) explore a dynamic ensemble of conformations and yet retain a functional role inside the cell. However, the correlation of backbone chain dynamics of an IDP correlated with its cellular function is not fully understood. Here in this work we analyze the MD simulation trajectories (12500 timesteps of total 10 nanosecond duration) of one ordered protein (catalytic domain of MutY from E. Coli, pdb code: 1MUN), one partially ordered protein (Apoptosis regulator Bcl-xL, 1LXL) and four IDPs (Brak/CXCL14, 2HDL; sub-domain of staphylococcal nuclease, 2SOB; F6 subunit of ATP synthase, 1VZS and Tyrosyl tRNA synthestase, 1JH3). The analysis included distance variations between chosen multiple points in the protein backbone, probability distributions of the measured distances and their velocities, and full width half maxima of these probability distributions. The results from the analysis yielded a quantitative measure of dynamics at loop regions in comparison to helix and strand regions. In addition the distance probability distributions of loop regions in IDPs specifically displayed multimodal character indicating distinct preferences for certain distances. This was in contrast to velocity probability distributions which were always of unimodal nature for all the six proteins. Further, we attempted to quantify the randomness in disordered chain dynamics by computing the Boltzmann entropy for all c-alpha atoms in each of the proteins. This entropy value for a given c-alpha atom correlated with its wandering ability in space. Disorder-order transition regions were spotted from the created protein movies and analyzed quantitatively by constructing Ramachandran plots for those regions across all time steps. Such regions included lysine residues previously speculated to be involved in post-translational modifications in F6 unit of ATP synthase and RNA binding domain in Tyrosyl tRNA synthestase.