Examining the assumptions underlying continuum-solvent models.

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

SUBMITTER: Harris RC 

PROVIDER: S-EPMC5340276 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature