Improving p<i>K</i>_a Predictions with Reparameterized Force Fields and Free Energy Calculations.

ABSTRACT: Given the growing interest in designing targeted covalent inhibitors, methods for rapidly and accurately probing pK_as─and, by extension, the reactivities─of target cysteines are highly desirable. Complementary to cysteine, histidine is similarly relevant due to its frequent presence in protein active sites and its unique ability to exist in two tautomeric states. Here, we demonstrate that nonequilibrium free energy calculations can accurately determine the pK_a values of both residues, often outperforming conventional predictors. Importantly, we find that (1) increasing the van der Waals radius of cysteine's sulfur atom, (2) modifying the backbone charges of histidine, and (3) introducing effective polarization by downscaling the side chain partial charge

SUBMITTER: Wilson CJ 

PROVIDER: S-EPMC12020373 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature