砷(Ⅲ)对p53突变蛋白活性恢复作用的太赫兹物理机制

Terahertz physical mechanism of arsenic(Ⅲ)restoring p53 mutant protein activity

通过小分子配体结合(如砷剂)来恢复p53突变蛋白活性是抑癌蛋白靶向治疗的重要策略,但p53蛋白在功能恢复过程中的分子集体动力学变化及其作用等机制基础尚不清楚.本文基于全原子弹性网络模型的正则模式分析了p53蛋白位于太赫兹频率的低频集体振动模式,以期解析砷(Ⅲ)对p53突变蛋白功能恢复作用所涉及的物理机理.结果表明,在砷(Ⅲ)配体结合后p53突变蛋白的DNA结合域的最低频率集体振动模式得到了有效恢复.进一步从原子骨架波动和太赫兹频率振动模态统计的角度分析了p53蛋白分子功能恢复的运动特征,并基于残基动力学相关性讨论了其运动耦合机理.本文从太赫兹生物物理的角度揭示了砷(Ⅲ)对p53蛋白活性恢复的可能机制,为蛋白分子低频运动特性与蛋白功能之间的联系提供了新的证据.

Recovering the protein activity of p53 mutants through small molecule ligand binding(eg.arsenic)is an important strategy for tumor suppressor therapy.However,the mechanistic basis on the changes of collective dynamics and their roles of p53 protein in functional recovery process has not been fully elucidated.Herein,the normal mode calculations based on all-atom elastic network model are employed to characterize the terahertz low frequency motions of core DNA-binding domain(p53C)which is essential for p53 protein activities in transcriptional transactivation.We find that the lowest-frequency collective vibration mode of the p53C mutant is effectively restored by the binding of arsenic(Ⅲ)ligand.In R249S mutant,the L1 loop is stabilized through restricting the swing-out movement.The results obtained from atomic backbone fluctuations suggest that the arsenic binding can significantly improve the L1 loop and L2 loop fluctuations.The statistical analysis of low frequency vibration mode reflects that the arsenic-bound R249 S mutant has an apparent recovery of frequency shift in the terahertz range.The residue-residue motion correlation also suggests that structural components binding to arsenic are dynamically coupled.In the H2 helix with arsenic-binding residues,the motions of C124,C135,M133 and C141,are correlated with the arsenic recovery.These results provide the terahertz biophysical mechanism for the recovery effect of arsenic(Ⅲ)on the p53 protein activity and new evidence for the coupling of the low-frequency vibration characteristics of protein structures with its function,thus giving a new physical insight into the p53 related cancer therapies.