Shandong Key Laboratory of Biophysics, Institute of Biophysics, Dezhou University, Dezhou 253023, China.
Laoling People's Hospital, Dezhou 253600, China.
Molecules. 2022 Aug 30;27(17):5596. doi: 10.3390/molecules27175596.
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.
开关结构域的构象变化显著影响 NRAS 的活性。进行了三次独立副本的高斯加速分子动力学（GaMD）模拟，以破译 G13D、Q16R 和 C118S 对 GDP 结合态 NRAS 构象转化的影响。均方根波动和动力学互相关图谱的分析表明，与效应物结合的 NRAS 开关结构域的结构灵活性和运动模式因 G13D、Q61R 和 C118S 突变而发生了很大改变。自由能景观（FEL）表明，突变诱导 NRAS 进入更多的能量状态，而不是 GDP 结合态 WT NRAS，导致开关结构域的高度无序。FEL 还表明，进入 GDP 结合区域的不同数量的钠离子补偿了突变引起的静电环境变化，特别是对于 G13D。GDP 残基相互作用表明，开关结构域的无序归因于 GDP 与两个残基 V29 和 D30 之间不稳定的氢键。这项工作有望提供有关开关结构域构象变化的能量基础和动力学的信息，有助于深入理解 NRAS 在抗癌治疗中的靶标作用。
