An equilibrium constant pH molecular dynamics method for accurate prediction of pH-dependence in protein systems: Theory and application

Computational modeling and simulation of biomolecular systems at their functional pH ranges requires an accurate approach to exploring the pH dependence of conformations and interactions. Here we present a new approach - the Equilibrium Constant pH (ECpH) method - to perform conformational sampling of protein systems in the framework of molecular dynamics simulations in an N, P, T-thermodynamic ensemble. The performance of ECpH is illustrated for two proteins with experimentally determined conformational responses to pH change: the small globular water-soluble bovine b-lactoglobulin (BBL), and the dimer transmembrane antiporter CLC-ec1 Cl-/H+. We show that with computational speeds comparable to equivalent canonical MD simulations we performed, the ECpH trajectories reproduce accurately the pH-dependent conformational changes observed experimentally in these two protein systems, some of which were not seen in the corresponding canonical MD simulations. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=153 SRC="FIGDIR/small/394015v1_ufig1.gif" ALT="Figure 1"> View larger version (79K): org.highwire.dtl.DTLVardef@b9c6bdorg.highwire.dtl.DTLVardef@a6d0d3org.highwire.dtl.DTLVardef@1d7fb23org.highwire.dtl.DTLVardef@a8f760_HPS_FORMAT_FIGEXP M_FIG Table of Contents artwork C_FIG