biostudies-literatureUnknown6(2)Hu ZKRAS 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 aJACS Au830-846https://www.ebi.ac.uk/biostudies/studies/S-EPMC12933348biostudies-literatureImpact of KRAS-G12 Mutations on the KRAS-GTP Bound Conformational Dynamics: Structure, Free Energy Barriers and Drugging Pockets.PMC12933348Sha ZHu ZGuo SJTao SCMarti JfalseImpact of KRAS-G12 Mutations on the KRAS-GTP Bound Conformational Dynamics: Structure, Free Energy Barriers and Drugging Pockets.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 a2026-01-01T00:00:00Z2026 Feb2026-07-16T22:58:19.047Z2026-07-12T03:09:34.131ZS-EPMC129333484175585110.1021/jacsau.5c01097