Examining the Assumptions Underlying Continuum-Solvent Models

摘要

Continuum-solvent models (CSMs) have successfully predicted many quantities, including the solvation-free energies (Delta G) of small molecules, but they have not consistently succeeded at reproducing experimental binding free energies (Delta Delta G), especially for protein protein complexes. Several CSMs break Delta G into the free energy (Delta G(vdw)) of inserting an uncharged molecule into solution and the free energy (Delta G(el)) gained from charging. Some further divide Delta G(vdw) into the free energy (Delta G(rep)) of inserting a nearly hard cavity into solution and the free energy (Delta G(att)) gained from turning on dispersive interactions between the solute and solvent. We show that for 9 protein-protein complexes neither Delta G(rep) nor Delta G(vdw), was linear in the solvent-accessible area A, as assumed in many CSMs, and the corresponding components of Delta Delta G were not linear in changes in A. We show that linear response theory (LRT) yielded good estimates of Delta G(att) and Delta Delta G(att), but estimates of Delta Delta Gatt obtained from either the initial or final configurations of the solvent were not consistent with those from LRT. The LRT estimates of Delta G(el) differed by more than 100 kcal/mol from the explicit solvent model's (ESM's) predictions, and its estimates of the corresponding component (Delta Delta G(el)) of Delta Delta G differed by more than 10 kcal/mol. Finally, the Poisson-Boltzmann equation produced estimates of Delta G(el) that were correlated with those from the ESM, but its estimates of Delta Delta G(el) were much less so. These findings may help explain why many CSMs have not been consistently successful at predicting Delta Delta G for many complexes, including protein-protein complexes.