Protein molecular dynamics with the generalized Born/ACE solvent model

Implicit solvent models are increasingly important for the study of protein s in aqueous solution. Here, the generalized Born (GB) solvent polarization model as implemented in the analytical ACE potential [Schaefer and Karplus (1996) J Phys Chem 100:1578] is used to perform molecular dynamics simulat ions of two small, homologous proteins: the immunoglobulin-binding domain o f streptococcal protein G and the Ras binding domain of Raf. Several model parameterizations are compared through more than 60 ns of simulation. Resul ts are compared with two simpler solvent models-an accessible surface area model and a distant-dependent dielectric model, with finite-difference Pois son calculations, with existing explicit solvent simulations, and with expe rimental data. The simpler models yield stable but distorted structures. Th e best GB/ACE implementation uses a set of atomic Voronoi volumes reported recently, obtained by averaging over a large database of crystallographic p rotein structures. A 20% reduction is applied to the volumes, compensating in an average sense for an excessive de-screening of individual charges inh erent in the ACE self-energy and for an undersolvation of dipolar groups in herent in the GB screening function. This GB/ACE parameterization yields st able trajectories on the 0.5-1-ns time scale that deviate moderately (simil ar to1.5-2.5 Angstrom) from the X-ray structure, reproduce approximately th e surface distribution of charged, polar, and hydrophobic groups, and repro duce accurately backbone flexibility as measured by amide NMR-order paramet ers. Over longer time scales (1.5-3 ns), some of the protein G runs escape from the native energy basin and deviate strongly (3 Angstrom) from the nat ive structure. The conformations sampled during the transition out of the n ative energy basin are overstabilized by the GB/ACE solvation model, as com pared with a numerical treatment of the full dielectric continuum model. (C ) 2001 Wiley-Liss, Inc.