Figure 3. Kinetics of the c-src kinase activation.

MSM of the kinase conformational change reveals novel intermediate states along the activation pathway and provide a measure of the activation/deactivation timescales. (A) Variation of key structural metrics as a function of time along the activation trajectory obtained using the MSM. MSM trajectories are calculated using a kinetic Monte Carlo algorithm to generate a trajectory of (τ=5 ns) microstate jumps, and selecting at random (uniformly) a simulation snapshot to report observables at each time step. RMSD of the activation loop is calculates using heavy atoms of residues 404-424. The following atoms were used for the calculations of distances between residues: Lys295(NZ atom in the ${\text{NH}}_3^{+}$ group), Glu310 (CD atom in the COO⁻ group) and Arg409 (CZ atom in the Guanidinium group). Different colors represent the different conformational states of the c-src kinase. Inactive(B), intermediate states I₁ (C), I₂(D), and active(E) states are shown in magenta, green, black and blue respectively with active state also marked with an asterisk. (F) These four conformational states could be further subdivided into states with different conformations of DFG-motif and R-spine.