Protocols for Metallo- and Serine-β-Lactamase Free Energy Predictions: Insights from Cross-Class Inhibitors.

ABSTRACT: While relative binding free energy (RBFE) calculations using alchemical methods are routinely carried out for many pharmaceutically relevant protein targets, challenges remain. For example, open-source tools do not support the easy setup and simulation of metalloproteins, particularly when ligands directly coordinate to the metal site. Here, we evaluate the performance of RBFE methods for KPC-2, a serine-β-lactamase (SBL), and two nonbonded metal parameter setups for VIM-2, a metallo-β-lactamase (MBL) with two active site zinc ions. We tested two different ways of modeling the ligand-zinc interactions. First, a restraint-based approach, in which FF14SB zinc parameters are combined with harmonic restraints between the zincs and their coordinating residues. The second approach uses an upgrad

SUBMITTER: Guven JJ 

PROVIDER: S-EPMC11664573 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature