The switch states of the GDP-bound HRAS affected by point mutations: a study from Gaussian accelerated molecular dynamics simulations and free energy landscapes

Abstract

Point mutations play a vital role in the conformational transformation of HRAS. In this work, Gaussian accelerated molecular dynamics (GaMD) simulations followed by constructions of free energy landscapes (FELs) were adopted to explore the effect of mutations D33K, A59T and L120A on conformation states of the GDP-bound HRAS. The results from the post-processing analyses on GaMD trajectories suggest that mutations alter the flexibility and motion modes of the switch domains from HRAS. The analyses from FELs show that mutations induce more disordered states of the switch domains and affect interactions of GDP with HRAS, implying that mutations yield a vital effect on the binding of HRAS to effectors. The GDP-residue interaction network revealed by our current work indicates that salt bridges and hydrogen bonding interactions (HBIs) play key roles in the binding of GDP to HRAS. Furthermore, instability in the interactions of magnesium ions and GDP with the switch SI leads to the extreme disorder of the switch domains. This study is expected to provide the energetic basis and molecular mechanism for further understanding the function of HRAS.

Communicated by Ramaswamy H. Sarma

Keywords:

• HRAS
• Gaussian accelerated molecular dynamics
• free energy landscape
• principal component analysis
• interaction network

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by funding from Shandong Provincial Key Laboratory of Biophysics, Natural Science Foundation of Shandong Province Grant (ZR2019MA040, ZR2021MA069 and ZR2020ME231) and Key Research and Development Project of Shandong province (No. 2019GGX102050).