Metadynamics study of benzyltrimethylammonium binding free energy to EmrE protein in all atom molecular dynamics simulations.

Abstract

EmrE is a membrane protein found in bacteria such as E. coli that transports positively charged, aromatic toxins outside the cell. It is a parallel dimer and belongs to the small multidrug resistance (SMR) family. Although it is very small, 110 amino acids per monomer, its structure was not resolved at high resolution until recently. The toxin transport is associated with an alternating access movement of the protein monomers. The toxin binds to the protein while the two GLU14 residues of the EmrE are deprotonated in the high pH environment, and is released on the other side when a GLU14 is protonated in low pH. We use metadynamics to calculate the free energy of the binding path of benzyltrimethylammonium to EmrE in a model bacterial membrane. Two geometric reaction coordinates were chosen for the metadynamics runs, distance between center of mass of toxin and the binding site, the angle of the toxin plane with the z-axis. Our results indicate that the free energy of benzyltrimethylammonium binding to EmrE through a water-only path is about −40 kJ/mol. We have also used funnel metadynamics to observe the effect of lipid interaction with the toxin to the binding free energy.