Web-Based Interface for Brownian Dynamics Simulation of Ion Channels and Its Application to Vdac

Abstract

We have developed a web-based graphical user interface (GUI) for automated input/system generation of grand canonical Monte Carlo/Brownian dynamics (GCMC/BD) ion channel simulation in the CHARMM-GUI resource (www.charmm-gui.org/input/gcmcbd). The GCMC/BD GUI starts with reading a PDB structure and generates input files necessary for GCMC/BD simulations of ion channels in symmetric or asymmetric solutions at any transmembrane potential. The GCMC/BD GUI facilitates (1) an appropriate placement of membrane channels having various pore sizes and orientations in implicit membrane bathed in electrolyte solution, (2) calculation of ion accessible region and generation of a protein charge map, and (3) calculation of the steric and electrostatic potential maps. To illustrate its efficacy in preparing and simulating ion channels under various conditions, we used the GCMC/BD GUI to investigate ion transport through the voltage dependent anion channel (VDAC) which is the primary pathway for metabolites and electrolytes in the mitochondrial outer membrane. GCMC/BD simulations were performed for all twenty NMR structures of human VDAC isoform 1 (hVDAC1, PDB:2K4T) to examine the ion transport properties such as single-channel conductance and ion selectivity. Using the space-dependent diffusion constant from the molecular dynamics (MD) simulation, GCMC/BD simulation results show similar ion transport properties of hVDAC1s to those from the MD simulations. Also, the ion transport properties have been compared with experimental measurement and analyzed to emphasize the importance of electrostatic contribution from protein charges in determining the channel transport properties. Furthermore, GCMC/BD simulations of hVDAC1 mutants have been performed for detailed analysis on the variation of ion selectivity.