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.
Highlights
Ras proteins, a series of GTPases [1], play key roles in the regulation of cell proliferation, cell survival as well as cell motility [2,3], and are closely related to tumorigenesis [4,5,6,7,8,9]
During the last 150 ns, the root-mean-square deviation (RMSD) values for the wild type and mutation complexes were 3.48 ± 0.31 Å and 3.53 ± 0.25 Å, respectively, which showed no significant difference. This suggested that the overall conformation of H-RasR135K–NS1 complex adopted a similar topology to the wild type complex
We explored the unbinding of NS1 to H-Ras caused by R135K mutation using molecular dynamics (MD) simulations and dynamic network analysis
Summary
A series of GTPases [1], play key roles in the regulation of cell proliferation, cell survival as well as cell motility [2,3], and are closely related to tumorigenesis [4,5,6,7,8,9]. Ras can be characterized as the activator in the RAS-RAF-MEK-ERK pathway [28,29,30,31], and the activation of the downstream Raf proteins requires the dimerization of Ras [30,31]. In their active forms, Ras-GTP complexes can form dimers with each other [24,32,33], which can subsequently recruit the Raf kinase. Together with the advances of structural biology and allostery, interacting with the allosteric sites of Ras has been established as an alternative method for the Ras-targeting treatments [11,28]
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