A STUDY OF CORRELATED PROTEIN MOTIONS BY NORMAL MODE ANALYSES AND MOLECULAR DYN

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 相关的蛋白质运动具有重要的功能意义，一直是各种实验和计算研究的目标。分子动力学(MD)模拟和简正波分析(NMA)都能够提供有关蛋白质内部动力学的信息。主成分分析(PCA)从蛋白质构象空间(通常是MD模拟轨迹的一段)的有限采样开始，通过对角化相关原子基团的协方差矩阵来梳理相关运动。振动模式的方向和幅度分别由所得到的特征向量和相应的特征值来表示。另一方面，基于蛋白质能量面的调和假设，简正波分析(NMA)通过对角化包含蛋白质能量面二阶导数的海森矩阵得到相关运动的方向和幅度。由于计算资源的限制，在不同分辨率下的NMA方法，从最简单弹性网络模型(ENM)、块简正模(BNM)到经典的全原子简正模方法，都比耗时的基于MD的主元分析方法更常用。然而，能量面的调和假设和隐含的溶剂处理使得NMA很难重现蛋白质动力学经常扩散和非调和的性质。在这里，我建议对选定的高分辨率X射线结构进行NMA和MD并行模拟，并将这两种计算方法的结果与实验确定的参数进行比较，包括各向同性振动幅度和各向异性振动方向性。预计基于MD的主成分分析将比NMA更接近实验观测。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Correlated protein motions are of great functional significance and have been the target of various experimental and computational studies. Both molecular dynamics (MD) simulation and normal mode analysis (NMA) are able to provide information about the internal protein dynamics. Starting from a limited sampling of the protein conformation space, usually a section of MD simulation trajectory, principal component analysis (PCA, or essential dynamics) teases out the correlation motions through a diagonalization of the covariance matrix for the relevant atom group. The direction and amplitude of the vibrational modes are represented by the resulting eigenvectors and the corresponding eigenvalues, respectively. On the other hand, based on a harmonic assumption of the protein energy surface, normal mode analysis (NMA) yields the direction and amplitude of the correlated motion through diagonalization of the Hessian matrix, which contains the second derivative of the protein energy surface. Due to a limitation of computational resources, NMA approaches at different resolutions, from simplest elastic network model (ENM), block normal mode (BNM), to the classical all-atom normal mode methods, have been used more often than the time consuming MD-based PCA approach. However, the harmonic assumption of the energy surface and the implicit treatment of solvent make the NMA difficult to reproduce the often diffusive and anharmonic nature of protein dynamics. Here I propose to carry out parallel NMA and MD simulations on selected high resolution X-ray structures and comparing the results from both computational approaches to the experimentally determined parameters, including the isotropic vibrational amplitudes and anisotropic vibrational directionality. It is expected that MD-based PCA would bring a closer match to the experimental observations than does NMA.