Conformational transformation of switch domains in GDP/K-Ras induced by G13 mutants: An investigation through Gaussian accelerated molecular dynamics simulations and principal component analysis

Mutations in K-Ras are involved in a large number of all human cancers, thus, K-Ras is regarded as a promising target for anticancer drug design. Understanding the target roles of K-Ras is important for providing insights on the molecular mechanism underlying the conformational transformation of the switch domains in K-Ras due to mutations. In this study, multiple replica Gaussian accelerated molecular (MR-GaMD) simulations and principal component analysis (PCA) were applied to probe the effect of G13A, G13D and G13I mutations on conformational transformations of the switch domains in GDP-associated K-Ras. The results suggest that G13A, G13D and G13I enhance the structural flexibility of the switch domains, change the correlated motion modes of the switch domains and strengthen the total motion strength of K-Ras compared with the wild-type (WT) K-Ras. Free energy landscape analyses not only show that the switch domains of the GDP-bound inactive K-Ras mainly exist as a closed state but also indicate that mutations evidently alter the free energy profile of K-Ras and affect the conformational transformation of the switch domains between the closed and open states. Analyses of hydrophobic interaction contacts and hydrogen bonding interactions show that the mutations scarcely change the interaction network of GDP with K-Ras and only disturb the interaction of GDP with the switch (SW1). In summary, two newly introduced mutations, G13A and G13I, play similar adjustment roles in the conformational transformations of two switch domains to G13D and are possibly utilized to tune the activity of K-Ras and the binding of guanine nucleotide exchange factors. Mutations in G13 site can tune the activity of K-Ras and binding of effectors. [Display omitted] •Gaussian accelerated molecular dynamics is adopted to improve conformational sampling of K-Ras.•Free energy landscapes are used to decipher energetic basis of mutation-mediated effect on the activity of K-Ras.•Principal component analysis is utilized to probe conformational changes of K-Ras due to mutations.