论文标题
单体和二聚体野生型和突变胰岛素的动力学和红外光谱
The Dynamics and Infrared Spectrocopy of Monomeric and Dimeric Wild Type and Mutant Insulin
论文作者
论文摘要
野生型和突变体胰岛素单体和二聚体中-CO标记的红外光谱和动力学是通过使用经过验证的力场的分子动力学模拟来表征的。发现在酰胺I-I振动区域中单体和二聚体形成的光谱与残基B24-B26和D24-D26不同，这与激素的二聚化有关。同样，光谱特征在位置B24的突变从苯丙氨酸中变化 - 在许多生物体中是保守的，已知在胰岛素聚集中起着核心作用 - 呈丙氨酸或甘氨酸。使用三种不同的方法来确定频率轨迹 - 在有效的一维势能曲线，瞬时正常模式以及使用参数化频率图上求解核schrödinger方程 - 导致相同的总体结论。单体WT和突变胰岛素的光谱反应与它们各自的二聚体的光谱反应以及二聚体中两个单体的光谱也不相同。对于WT和F24A和F24G单体的光谱偏移为$ \ sim 20 $ cm $^{ - 1} $，用于残基（B24至B26），位于二聚体接口上。尽管二聚体的晶体结构是对称同型二聚体的晶体结构，但在纳秒时间尺度上，这两个单体动态不相等。以及对WT热力学稳定性的较早工作以及相同的突变体的结合，结合计算和实验红外光谱法提供了一种表征改进胰岛素的聚集状态和二聚能的潜在强大方法。
The infrared spectroscopy and dynamics of -CO labels in wild type and mutant insulin monomer and dimer are characterized from molecular dynamics simulations using validated force fields. It is found that the spectroscopy of monomeric and dimeric forms in the region of the amide-I vibration differs for residues B24-B26 and D24-D26, which are involved in dimerization of the hormone. Also, the spectroscopic signatures change for mutations at position B24 from phenylalanine - which is conserved in many organisms and known to play a central role in insulin aggregation - to alanine or glycine. Using three different methods to determine the frequency trajectories - solving the nuclear Schrödinger equation on an effective 1-dimensional potential energy curve, instantaneous normal modes, and using parametrized frequency maps - lead to the same overall conclusions. The spectroscopic response of monomeric WT and mutant insulin differs from that of their respective dimers and the spectroscopy of the two monomers in the dimer is also not identical. For the WT and F24A and F24G monomers spectroscopic shifts are found to be $\sim 20$ cm$^{-1}$ for residues (B24 to B26) located at the dimerization interface. Although the crystal structure of the dimer is that of a symmetric homodimer, dynamically the two monomers are not equivalent on the nanosecond time scale. Together with earlier work on the thermodynamic stability of the WT and the same mutants it is concluded that combining computational and experimental infrared spectroscopy provides a potentially powerful way to characterize the aggregation state and dimerization energy of modified insulins.
