MD INTERPRETATION OF SNASE MOTIONAL PARAMETERS

这项拟议研究的目标是开发准确模拟和解释蛋白质中原子水平运动的核磁共振弛豫数据的技术。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价值，特别是在药物设计方面。核磁共振是表征原子水平运动的最广泛有用的实验方法，但实验数据需要解释，分子动力学模拟可以提供这种解释。拟议的研究集中在葡萄球菌核酸酶的侧链动力学，葡萄球菌核糖核酸酶是一种可以获得核磁共振侧链松弛数据的小蛋白质。以前的模拟主要集中在蛋白质的主干动力学上，因为可以获得更多的核磁共振数据来描述这些运动，并且所监测的运动(N-H和Calpha-H键向量)的时间尺度更短。拟议的研究将通过(1)在使用最真实的溶剂化方法时，基于结晶肽和溶剂化葡萄球菌核酸酶的模拟，建立刺激和核磁共振松弛数据之间可能的一致性水平，(2)表征侧链运动参数的更接近的溶剂化模型的影响，因为这样的方法可以实现其他不可行的计算，(3)改进识别侧链柔性的重要自由度和将迁移率的程度与核磁共振序参数定量关联的方法，以及(4)开发将构象熵与侧链运动的序参数相关联的方法。

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.