Impact of KRAS-G12 Mutations on the KRAS-GTP Bound Conformational Dynamics: Structure, Free Energy Barriers and Drugging Pockets.

ABSTRACT: KRAS is among the most frequently mutated oncogenes in human cancers, with codon 12 representing a dominant hotspot. Despite decades of study, the atomic-level conformational dynamics of KRAS and its G12 mutations remain insufficiently resolved, posing a central barrier to rational drug discovery. Elucidating these dynamics is critical for revealing hidden druggable pockets and enabling the development of mutation-specific inhibitors. Here, we delineate the impact of KRAS G12 mutations on conformational dynamics and GTP binding by performing microsecond-scale, well-tempered metadynamics simulations. This approach yielded precise free energy landscapes that expose mutation-specific alterations to structural states. By introducing biologically meaningful collective variables, including key a

SUBMITTER: Hu Z 

PROVIDER: S-EPMC12933348 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature