An in-silico comparative analysis of KRAS mutant interactions with wild-type Isoforms HRAS and NRAS

Abstract

Abstract RAS genes code for KRAS, HRAS, and NRAS which are three frequent mutated oncogenes responsible for cancer development. When RAS GTPases are deregulated, tumorigenesis is one of the most significant outcomes. The binding of the three isoforms, especially when mutated, has not been extensively studied to design an inhibitory drug. Some recent studies have noted important interactions between the isoforms that impact the oncogenic strength of the others when they are mutated. In this study, I use molecular dynamics simulations to examine the binding patterns of KRAS when interacting individually with HRAS and NRAS. The binding sites of the isoforms with KRAS are similar to the regions involved in the GDP/GTP binding and the site of KRAS dimerization. Therefore, isoform interaction may serve as a way of inhibiting KRAS’ actions. This study enhances the understanding of inhibiting the development of RAS-driven cancers via a unique isoform interaction approach only recently discovered to be possible, to serve as a therapeutic approach. I developed a blueprint of the interactions which would benefit the creation of KRAS mutant specific and pan-KRAS mutant inhibitory drugs that are similar to the isoform interactions. My results support a mechanism of direct interaction inhibition of mutant KRAS when in contact with WT-HRAS and WT-NRAS at the isoforms’ hypervariable region binding to KRAS’s G-domain.