Deciphering Conformational Changes of the GDP-Bound NRAS Induced by Mutations G13D, Q61R, and C118S through Gaussian Accelerated Molecular Dynamic Simulations.

The conformational changes in switch domains significantly affect the activity of NRAS. Gaussian-accelerated molecular dynamics (GaMD) simulations of three separate replicas were performed to decipher the effects of G13D, Q16R, and C118S on the conformational transformation of the GDP-bound NRAS. The analyses of root-mean-square fluctuations and dynamics cross-correlation maps indicated that the structural flexibility and motion modes of the switch domains involved in the binding of NRAS to effectors are highly altered by the G13D, Q61R, and C118Smutations. The free energy landscapes (FELs) suggested that mutations induce more energetic states in NRAS than the GDP-bound WT NRAS and lead to high disorder in the switch domains. The FELs also indicated that the different numbers of sodium ions entering the GDP binding regions compensate for the changes in electrostatic environments caused by mutations, especially for G13D. The GDP-residue interactions revealed that the disorder in the switch domains was attributable to the unstable hydrogen bonds between GDP and two residues, V29 and D30. This work is expected to provide information on the energetic basis and dynamics of conformational changes in switch domains that can aid in deeply understanding the target roles of NRAS in anticancer treatment.