A thermodynamic cycle to predict the competitive inhibition outcomes of an evolving enzyme.

ABSTRACT: Understanding competitive inhibition at the molecular level is essential for unraveling the dynamics of enzyme-inhibitor interactions and predicting the evolutionary outcomes of resistance mutations. In this study, we present a framework linking competitive inhibition to alchemical free energy perturbation (FEP) calculations, focusing on E. coli dihydrofolate reductase (DHFR) and its inhibition by trimethoprim (TMP). Using thermodynamic cycles, we relate experimentally measured binding constants ( Ki and Km ) to free energy differences associated with wild-type and mutant forms of DHFR with a mean error of 0.9 kcal/mol, providing insights into the molecular underpinnings of TMP resistance. Our findings highlight the importance of local conformational dynamics in competitive inhibiti

SUBMITTER: Cetin E 

PROVIDER: S-EPMC11838402 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature