Accurate Hydrodynamic Modeling with the Boundary Element Method

Abstract

The integral equations of hydrodynamics are presented for both stick and slip boundary conditions, and results of computations including rigid amino acids are used to obtain a new interpretation of the significance of the hydration parameter used in hydrodynamic modeling. The dynamics of the protein surface perturbs water at that boundary, giving rise to additional viscous energy dissipation which is mimicked by a uniform solvation of 1.1 A thick with stick boundary conditions. BEST (Aragon SR, J Comput Chem 25:1191–12055, 2004) has been used to study 49 different proteins, ranging in molecular weight from 9 to 400 kDa, and we have shown that a model using a 1.1 A thick hydration layer describes all protein transport properties very well. Molecular dynamics (MD) simulation has been used to investigate the origin of a handful of significant discrepancies in some multimeric proteins. A preliminary study of dimeric α-chymotrypsin using approximate implicit water MD is presented. In addition I describe the successful validation of modern protein force fields, ff03 and ff99SB, for the accurate computation of solution structure in explicit water simulation for small proteins using trajectories around 10 ns duration. We have also studied a 150 kDa flexible monoclonal IgG antibody, trastuzumab, with multiple independent trajectories encompassing over 320 ns of simulation. The close agreement within experimental error of the computed and measured properties allows us to conclude that MD does produce structures typical of those in solution and that flexible molecules can be properly described using the method of ensemble averaging over a trajectory.