AUTHOR=Silverman Isaac , Gerber Michael , Shaykevich Aaron , Stein Yitzchak , Siegman Alexander , Goel Sanjay , Maitra Radhashree 

TITLE=Structural modifications and kinetic effects of KRAS interactions with HRAS and NRAS: an in silico comparative analysis of KRAS mutants

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=11

YEAR=2024

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2024.1436976

DOI=10.3389/fmolb.2024.1436976

ISSN=2296-889X

ABSTRACT=<p>The RAS genes which code for <italic>KRAS</italic>, <italic>HRAS</italic>, and <italic>NRAS</italic> are three of the most frequently mutated oncogenes responsible for cancer deaths. Tumorigenesis is one of the most significant outcomes of deregulation of RAS GTPases. Although the structures have been extensively studied, there is still more to be discovered about the actual binding conformations of the three isoforms, especially when mutated, to design an inhibitory drug. Recent studies have identified important interactions between the three isoforms that affect the oncogenic strength of the others when they are mutated. In this study, we utilize molecular dynamics simulations to examine the modifications of the structural property, mechanism, and kinetic energy of <italic>KRAS</italic> when interacting individually and with <italic>HRAS</italic> and <italic>NRAS</italic>. Notably, we found that WT-<italic>KRAS</italic>’ orientation when bound to WT-<italic>HRAS</italic> vs. WT-<italic>NRAS</italic> is rotated 180°, with mutants demonstrating a similar binding pattern. The binding sites of the isoforms with <italic>KRAS</italic> share similarities with those involved in the GDP/GTP active site and site of <italic>KRAS</italic> dimerization. Thus, the isoform interaction can serve as an inhibitory method of <italic>KRAS</italic> actions. This study advances the understanding of inhibiting RAS-driven cancers through a novel isoform interaction approach only recently discovered, which has been proven to be an effective alternate therapeutic approach. We developed a blueprint of the interaction which would be beneficial in the development of <italic>KRAS</italic> mutant-specific and pan<italic>-KRAS</italic> mutant inhibitory drugs that mimic the isoform interactions. Our results support the direct interaction inhibition mechanism of mutant <italic>KRAS</italic> when bound to WT-<italic>HRAS</italic> and WT-<italic>NRAS</italic> by the isoforms’ hypervariable region binding to the G-domain of <italic>KRAS</italic>. Furthermore, our results support the approach of reducing the effects of oncogenic <italic>KRAS</italic> by altering the concentration of the isoforms or a drug alternative based on the overall structural and kinetic stability, as well as the binding strength of the mutant-isoform complexes.</p>