Mutations influence the conformational dynamics of the GDP/KRAS complex

Abstract

Mutations near allosteric sites can have a significant impact on the function of KRAS. Three specific mutations, K104Q, G12D/K104Q, and G12D/G75A, which are located near allosteric positions, were selected to investigate the molecular mechanisms behind mutation-induced influences on the activity of KRAS. Gaussian accelerated molecular dynamics (GaMD) simulations followed by the principal component analysis (PCA) were performed to improve the sampling of conformational states. The results revealed that these mutations significantly alter the structural flexibility, correlated motions, and dynamic behavior of the switch regions that are essential for KRAS binding to effectors or regulators. Furthermore, the mutations have a significant impact on the hydrogen bonding interactions between GDP and the switch regions, as well as on the electrostatic interactions of magnesium ions (Mg²⁺) with these regions. Our results verified that these mutations strongly influence the binding of KRAS to its effectors or regulators and allosterically regulate the activity. We believe that this work can provide valuable theoretical insights into a deeper understanding of KRAS function.

Communicated by Ramaswamy H. Sarma

Keywords:

• GaMD simulation
• GTP/KRAS complex
• free energy landscapes
• conformational dynamics

Authors’ contributions

Conceptualization, C.S., Z.Y. and G.H.; methodology, C.S. and G.H.; validation, J.Y., M.W., X.X., and Z.Z.; formal analysis, C.S.; investigation, X.X. and M.W.; data curation, J.Y., X.X., Z.Z., and Y.H; writing—original draft preparation, C.S. and Z.Y.; writing—review and editing, C.S., Y.H. and G.H.; visualization, C.X.; supervision, G.H.; project administration, C.S.; funding acquisition, G.H. All authors have read and agreed to the published version of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This research was partially supported by funding from the National Natural Science Foundation of China (32171249 and 62071085), Dezhou University (HXKT2023065 and 2022KFKT004) and the Youth Innovation Team Lead-education Project of Shandong Educational Committee.