The seven metastable states identified by the Markov state model.

In the middle is the time-lagged independent component analysis (TICA) plot showing seven clusters, each of which corresponds to one metastable state (I–VII). The metastable states are classified by borderlines, and the “microstates” (dots) in each metastable state are colored with the same color. The seven boxes around the middle describe the seven metastable states found in the MSM analysis, each box illustrating three representative protein conformations (generated using MSM), which identify the residue 12 (orange), and also the switch-I (red) and switch-II (blue) regions depicted by their backbone’s molecular surface (dots). In each metastable state, the occupation percentage by wild-type and individual mutants is displayed next to the conformations. For each case (wild-type, G12D, G12V, G12R), normalization of the percentages is done such that the sum over the seven metastable states adds up to 100%.