Mutational landscape of K-Ras substitutions at 12th position-a systematic molecular dynamics approach

Abstract

K-Ras is a small GTPase and acts as a molecular switch by recruiting GEFs and GAPs, and alternates between the inert GDP-bound and the dynamic GTP-bound forms. The amino acid at position 12 of K-Ras is a hot spot for oncogenic mutations (G12A, G12C, G12D, G12R, G12S, and G12V), disturbing the active fold of the protein, leading to cancer development. This study aimed to investigate the potential conformational changes induced by these oncogenic mutations at the 12^th position, impairing GAP-mediated GTP hydrolysis. Comprehensive computational tools (iStable, FoldX, SNPeffect, DynaMut, and CUPSAT) were used to evaluate the effect of these six mutations on the stability of wild type K-Ras protein. The docking of GTP with K-Ras was carried out using AutoDock4.2, followed by molecular dynamics simulations. Furthermore, on comparison of binding energies between the wild type K-Ras and the six mutants, we have demonstrated that the G12A and G12V mutants exhibited the strongest binding efficiency compared to the other four mutants. Trajectory analyses of these mutations revealed that G12A encountered the least deviation, fluctuation, intermolecular H-bonds, and compactness compared to the wildtype, which was supported by the lower Gibbs free energy value. Our study investigates the molecular dynamics simulations of the mutant K-Ras forms at the 12^th position, which expects to provide insights about the molecular mechanisms involved in cancer development, and may serve as a platform for targeted therapies against cancer.

Communicated by Ramaswamy H. Sarma

Keywords:

• K-Ras
• cancer
• mutation
• molecular docking
• molecular dynamics simulation

Acknowledgements

Mr. Udhaya Kumar. S, one of the authors, gratefully acknowledges the Indian Council of Medical Research (ICMR), India, for providing him a Senior Research Fellowship [ISRM/11(93)/2019]. The authors thank the management of VIT for providing the facilities and the encouragement to carry out this work.

Author's contribution

SUK, HZ, and GPDC were involved in the design of the study. SUK and RB were involved in the data collection and conducted the experiment. SUK, RB, and TKD were involved in the acquisition, analysis, interpretation of the results and drafting the manuscript. GPDC and HZ supervised the entire study and were involved in study design, acquisition, analysis, and interpretation of the data, and drafting the manuscript. All authors edited and approved the submitted version of the article.

Disclosure statement

No conflicts of interest exist.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.