Targeting electrostatic interactions in accelerated molecular dynamics with application to protein partial unfolding.

Accelerated molecular dynamics (aMD) is a promising sampling method to generate an ensemble of conformations and to explore the free energy landscape of proteins in explicit solvent. Its success resides in its ability to reduce barriers in the dihedral and the total potential energy space. However, aMD simulations of large proteins can generate large fluctuations of the dihedral and total potential energy with little conformational changes in the protein structure. To facilitate wider conformational sampling of large proteins in explicit solvent, we developed a direct intrasolute electrostatic interactions accelerated MD (DISEI-aMD) approach. This method aims to reduce energy barriers within rapidly changing electrostatic interactions between solute atoms at short-range distances. It also results in improved reconstruction quality of the original statistical ensemble of the system. Recently, we characterized a pH-dependent partial unfolding of diphtheria toxin translocation domain (T-domain) using microsecond long MD simulations. In this work, we focus on the study of conformational changes of a low-pH T-domain model in explicit solvent using DISEI-aMD. On the basis of the simulations of the low-pH T-domain model, we show that the proposed sampling method accelerates conformational rearrangement significantly faster than multiple standard aMD simulations and microsecond long conventional MD simulations.