MD INTERPRETATION OF SNASE MOTIONAL PARAMETERS

拟议研究的目标是开发技术，用于精确模拟和解释蛋白质原子级运动的NMR弛豫数据。表征蛋白质的原子水平动力学对于理解分子生物学中的许多过程至关重要，包括配体结合，蛋白质识别和蛋白质折叠，因此具有广泛的医学应用性，特别是药物设计。核磁共振是表征原子水平运动的最广泛的实验方法，但实验数据需要解释，分子动力学模拟可以提供。拟议的研究集中在葡萄球菌核酸酶，一个小蛋白质的NMR侧链弛豫数据的侧链动力学。以前的模拟主要集中在蛋白质的骨架动力学上，因为更多的NMR数据可用于这些运动，并且监测的运动（N-H和Calpha-H键矢量）的时间尺度缩短了。拟议的研究将通过以下方式进行：（1）基于结晶肽和溶剂化葡萄球菌核酸酶的模拟，在使用最现实的溶剂化方法时，建立刺激和NMR弛豫数据之间可能的一致性水平，（2）表征侧链运动参数的更近似溶剂化模型的影响，因为这种方法可以实现否则不可行的计算，（3）改进用于识别侧链柔性的重要自由度和将移动度与NMR序参数定量关联的方法，以及（4）开发用于将构象熵与侧链运动的序参数关联的方法。

The goal of the proposed research is to develop techniques for the accurate simulation and interpretation of NMR relaxation data for atomic- level motions in proteins. Characterizing the atomic-level dynamics of proteins is critical to understanding many processes in molecular biology, including ligand binding, protein recognition, and protein folding, and thus has wide medicinal applicability, particularly to drug design. NMR is the most broadly useful experimental method for characterizing atomic- level motions, but the experimental data require interpretation, which molecularly dynamics simulation can provide. The proposed research focuses on the side-chain dynamics of staphylococcal nuclease, a small protein for which NMR side-chain relaxation data are available. Previous simulations have focused primarily on the backbone dynamics of proteins because more NMR data are available for these motions, and the time scale of the motions monitored (N-H and Calpha-H bond vectors) is shorted. The proposed research will proceed by (1) establishing the level of agreement possible between stimulation and NMR relaxation data when the most realistic solvation methods are used, based on simulations of crystalline peptides and of solvated staphylococcal nuclease, (2) characterizing the effect of more approximate solvation models of side-chain motional parameters, as such methods can enable otherwise unfeasible calculations, (3) refining methods for identifying the important degrees of freedom for side-chain flexibility and quantitatively relating the degree of mobility to NMR order parameters, and (4) developing methods for relating conformational entropies to order parameters for side-chain motions.