Characterization of the KRas G12D-inhibitor interactions by differential HDX-MS and molecular dynamics simulations.

ABSTRACT: Hydrogen-deuterium exchange (HDX) combined with mass spectrometry (MS) is a powerful technique for studying changes in protein structure and dynamics upon ligand binding. Protein-ligand complexes can result in increased protection of peptide-bond amides in HDX indicating protein structure stabilization. We have characterized the interaction of small-molecule inhibitors towards the KRas G12D oncoprotein by intact-protein and bottom-up HDX-MS, in combination with molecular dynamics (MD) simulations. Significant differences in HDX protection were detected upon inhibitor binding in the flexible switch-II pocket of the protein. MD simulations of the free and inhibitor-bound KRas G12D proteins also revealed changes in the hydrogen bond network of backbone amides in the switch-II region upon inhi

SUBMITTER: Petrotchenko EV 

PROVIDER: S-EPMC12362407 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature