Ion-Trapping in HCV P7 Hexameric Bundles - A Molecular Dynamics Simulation Study

Abstract

Viral channel forming proteins assemble into homo-oligomers when produced within the infected cells and full fill their role as diffusion-amplifier for ions across subcellular membranes. Alteration of the electrochemical gradients seems to be necessary and in some cases essential for the survival of the virus. Much is known about the structural features of many of the channels, dynamics data about oligomerization, assembly and ion diffusion within the assembled bundles is still lacking. The dynamics of physiological relevant ions, Na+, K+, Cl- and Ca2+ are monitored in the vicinity of hexameric bundles of p7 of Hepatitis C virus (HCV), strain 1a. The bundles are generated by a combination of docking approach and molecular dynamics simulations. Ion dynamics is recorded during multi 200 ns MD simulations of 1 M solutions. With a crucial residue, histidine-17, found to point into the lumen of the pore, protonation of this residue is altered and the effect on the ion dynamics monitored. While an 'unprotonated' p7 bundle allows Ca2+ to enter the lumen, it is exclusively the Cl- in case of a 'protonated' bundle.