Molecular Dynamics Simulations and Dynamic Network Analysis Reveal the Allosteric Unbinding of Monobody to H-Ras Triggered by R135K Mutation

International Journal of Molecular Sciences
Duan NiShaoyong Lu

Abstract

Ras proteins, as small GTPases, mediate cell proliferation, survival and differentiation. Ras mutations have been associated with a broad spectrum of human cancers and thus targeting Ras represents a potential way forward for cancer therapy. A recently reported monobody NS1 allosterically disrupts the Ras-mediated signaling pathway, but its efficacy is reduced by R135K mutation in H-Ras. However, the detailed mechanism is unresolved. Here, using molecular dynamics (MD) simulations and dynamic network analysis, we explored the molecular mechanism for the unbinding of NS1 to H-Ras and shed light on the underlying allosteric network in H-Ras. MD simulations revealed that the overall structures of the two complexes did not change significantly, but the H-Ras-NS1 interface underwent significant conformational alteration in the mutant Binding free energy analysis showed that NS1 binding was unfavored after R135K mutation, which resulted in the unfavorable binding of NS1. Furthermore, the critical residues on H-Ras responsible for the loss of binding of NS1 were identified. Importantly, the allosteric networks for these important residues were revealed, which yielded a novel insight into the allosteric regulatory mechanism of H-Ras.

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Citations

Sep 16, 2020·Physical Chemistry Chemical Physics : PCCP·Jianzhong ChenWeiliang Zhu
Feb 9, 2019·Journal of Enzyme Inhibition and Medicinal Chemistry·Xinyuan XuShaoyong Lu
Jun 25, 2019·Pharmacology & Therapeutics·Duan NiShaoyong Lu
Mar 1, 2019·Journal of Medicinal Chemistry·Shaoyong LuJian Zhang

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Methods Mentioned

BETA
GTPases
PCA
PISA

Software Mentioned

NetworkView
py
PISA ( Proteins , Interfaces , Structures and Assemblies )
VMD
MMPBSA
Amber
cpptraj

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