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 K-Ras. 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-RasG12D. Furthermore, characteristic decay times of SII fluctuations significantly increase after G12D mutation. We have further identified causal relationships between correlated residue pairs in K-RasG12D 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 K-Ras. Ours is arguably the first study that shows the causal relationships between residue pairs in K-RasG12D, relates them to the decay times and correlates their fluctuations.