SHORT COMMUNICATION Modeling Loop Reorganization Free Energies of Acetylcholinesterase: A Comparison of Explicit and Implicit Solvent Models

The treatment of hydration effects in protein dynamics simulations varies in model complexity and spans the range from the computationally intensive microscopic evaluation to simple dielectric screening of charge-charge interactions. This paper compares different solvent models applied to the problem of estimating the free-energy differencebetween two loop conformations in acetylcholinesterase. Molecular dynamics (MD) simulations were used to sample potential energy surfaces of the two basins with solvent treated by means of explicit and implicitmethods. Implicit solventmethods studied include the generalizedBorn (GB)model, atomic solvation potential (ASP), and the distancedependent dieletric constant. By using the linear response approximation (LRA), the explicit solvent calculations determined a free-energy difference that is in excellent agreement with the experimental estimate, while rescoring the protein conformationswithGBor thePoisson equation showed inconsistent and inferior results. While the approach of rescoring conformations fromexplicit water simulations with implicit solvent models is popular among many applications, it perturbs the energy landscape by changing the solvent contribution to microstates without conformational relaxation, thus leading to non-optimal solvation free energies. Calculations applying MD with a GB solvent model produced results of comparable accuracy as observed with LRA, yet the electrostatic free-energy terms were significantly different due to optimization on a potential energy surface favored by an implicit solvent reaction field. The simpler methods of ASP and the distance-dependent scaling of the dielectric constant both produced considerable distortions in the protein internal free-energy terms and are consequently unreliable. Proteins 2004;57:645–650. Published 2004Wiley-Liss, Inc.*