Oncogenic G12D mutation alters local conformations and dynamics of K-Ras

Abstract

K-Ras is the most frequently mutated protein in human tumors. Activating K-Ras mutations drive cancer initiation, progression and drug resistance, directly leading to nearly a million deaths per year. To understand the mechanisms by which mutations alter K-Ras function, we need to understand their effects on protein dynamics. However, despite decades of research, how oncogenic mutations in K-Ras alter its conformation and dynamics remain to be understood. Here, we present how the most recurrent K-Ras oncogenic mutation, G12D, leads to structural, conformational and dynamical changes that lead to constitutively active KRas. We have developed a new integrated MD simulation data analysis approach to quantify such changes in a protein and applied it to K-Ras. Our results show that G12D mutation induces strong negative correlations between the fluctuations of SII and those of the P-loop, Switch I (SI) and α3 regions in K-Ras G12D . Furthermore, characteristic decay times of SII fluctuations significantly increase after G12D mutation. We have further identified causal relationships between correlated residue pairs in K-Ras G12D and show that the correlated motions in K-Ras dynamics are driven by SII fluctuations, which have the strongest negative correlations with other protein parts and the longest characteristic decay times in mutant KRas. Ours is arguably the first study that shows the causal relationships between residue pairs in K-Ras G12D , relates them to the decay times and correlates their fluctuations.