Path sampling simulations reveal how the Q61L mutation restricts the dynamics of KRas

Abstract

The GTPase KRas is a signaling protein in networks for cell differentiation, growth, and division. KRas mutations can prolong activation of these networks, resulting in tumor formation. When active, KRas tightly binds GTP. Several oncogenic mutations affect the conversion between this rigid state and inactive, more flexible states. Detailed understanding of these transitions may provide valuable insights into how mutations affect KRas. Path sampling simulations, which focus on transitions, show KRas visiting several states, which are the same for wild type and the oncogenic mutant Q61L. Large differences occur when converting between these states, indicating the dramatic effect of the Q61L mutation on KRas dynamics. For Q61L a route to the flexible state is inaccessible, thus shifting the equilibrium to more rigid states. Our methodology presents a novel way to predict dynamical effects of KRas mutations, which may aid in identifying potential therapeutic targets.

Transition Path Sampling as Markov Chain Monte Carlo of Trajectories: Recent Algorithms, Software, Applications, and Future Outlook

“…Analysis of the switching behavior can be a useful test of convergence, [ 35 ] but can also be used to highlight differences in dynamics of related systems, such as mutations of a protein. [ 80 ]…”