Distinct dynamics and interaction patterns in H- and K-Ras oncogenic P-loop mutants

Proteins
Abdallah Sayyed-AhmadAlemayehu A Gorfe

Abstract

Despite years of study, the structural or dynamical basis for the differential reactivity and oncogenicity of Ras isoforms and mutants remains unclear. In this study, we investigated the effects of amino acid variations on the structure and dynamics of wild type and oncogenic mutants G12D, G12V, and G13D of H- and K-Ras proteins. Based on data from µs-scale molecular dynamics simulations, we show that the overall structure of the proteins remains similar but there are important differences in dynamics and interaction networks. We identified differences in residue interaction patterns around the canonical switch and distal loop regions, and persistent sodium ion binding near the GTP particularly in the G13D mutants. Our results also suggest that different Ras variants have distinct local structural features and interactions with the GTP, variations that have the potential to affect GTP release and hydrolysis. Furthermore, we found that H-Ras proteins and particularly the G12V and G13D variants are significantly more flexible than their K-Ras counterparts. Finally, while most of the simulated proteins sampled the effector-interacting state 2 conformational state, G12V and G13D H-Ras adopted an open switch state 1 conformation tha...Continue Reading

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Citations

Sep 16, 2020·Physical Chemistry Chemical Physics : PCCP·Jianzhong ChenWeiliang Zhu
Mar 25, 2019·Chemical Biology & Drug Design·Amit K GuptaAlemayehu A Gorfe
Aug 21, 2020·Cancer Metastasis Reviews·Gyula PálfyAndrás Perczel
Jun 21, 2017·The Journal of Biological Chemistry·Christian W JohnsonCarla Mattos
Aug 15, 2019·Scientific Reports·Sezen VatanseverZeynep H Gümüş
Jan 29, 2020·Computational and Structural Biotechnology Journal·Tatu Pantsar
May 13, 2021·The Journal of Physical Chemistry. B·Meryem ErenOzlem Keskin
Jun 8, 2021·Chemical Science·Dóra K MenyhárdAndrás Perczel
Mar 17, 2020·ACS Omega·Ana Rita CalixtoShina Caroline Lynn Kamerlin
Dec 4, 2019·Accounts of Chemical Research·Xin-Qiu Yao, Donald Hamelberg

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