胰岛素单体、二聚体、野生型和突变型的动力学和红外光谱
The Dynamics and Infrared Spectrocopy of Monomeric and Dimeric Wild Type and Mutant Insulin
摘要：
红外光谱和动力学的野生型和突变型胰岛素单体和二聚体的-CO标签的特点是从分子动力学模拟使用验证力场。据发现，光谱的单体和二聚体形式的酰胺-I振动的区域中不同的残基B24-B26和D24-D26，这是参与二聚化的激素。此外，光谱特征对于位置B24处的突变从苯丙氨酸（其在许多生物体中是保守的并且已知在胰岛素聚集中起核心作用）改变为丙氨酸或甘氨酸。使用三种不同的方法来确定频率轨迹--在有效一维势能曲线上求解核薛定谔方程、瞬时简正模和使用参数化频率图--得出了相同的总体结论。单体WT和突变体胰岛素的光谱响应与其各自的二聚体不同，并且二聚体中两种单体的光谱也不相同。对于WT和F24 A和F24 G单体，发现位于二聚化界面的残基（B24至B26）的光谱位移为$\sim 20$ cm $^{-1}$。虽然二聚体的晶体结构是对称同二聚体的晶体结构，但动态地，两个单体在纳秒时间尺度上是不等价的。与早期的WT和相同的突变体的热力学稳定性的工作，它的结论是，结合计算和实验红外光谱提供了一个潜在的强大的方式来表征的聚集状态和二聚化能量的修饰胰岛素。
英文摘要：
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.
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