Dynamics and Thermodynamics of Proteins by NMR and Computation

该奖项是根据2009年《美国复苏和再投资法案》(公法111-5)资助的，详细介绍了原子水平上的蛋白质动力学及其热力学影响，这对于理解蛋白质的稳定性和功能具有基本的生物物理意义。该项目的总体目标是开发新的方法来全面描述蛋白质的复杂动力学和热力学，并证明它们对具有生物重要性的分子系统的适用性。最近出现的越来越长的分子动力学模拟将被用来缩小模拟和实验核磁共振(NMR)参数之间的时间尺度差距，特别是残余偶极耦合和旋转框架弛豫速率。将对ms范围进行非常长的模拟，以与蛋白质主链和侧链的实验进行定量比较。一方面，这些信息将对分子力力场的准确性进行全面的评估，并指导其进一步优化。另一方面，它为解释这些实验的核磁共振参数提供了一种现实的微观方法。这些模拟还允许分析软自由度之间具有统计意义的相关运动，例如二面角，从而允许准确地提取构形熵。这些概念将在模型蛋白质系统上进行测试，并应用于蛋白质MDM2与抑制剂相互作用时的熵传递机制的实验和计算分析。这项研究的结果将为蛋白质的表征产生新的计算、统计热力学和核磁共振波谱概念，这将增强对蛋白质行为和功能的理解，并为具有新性质的蛋白质的工程提供输入。结果将以出版物的形式传播，并将通过公共网络服务器向生物物理学和生物分子核磁共振社区提供。该项目为佛罗里达州立大学(FSU)化学和生物化学系、FSU分子生物物理研究所和国家强磁场实验室(NHMFL)的研究生提供跨学科的培训和研究机会，这些学生中有相当数量的学生来自人口统计学上代表不足的群体。研究方法和成果将纳入生物物理学和生物分子光谱学的高级本科生和研究生课程。P.I.参与了NHMFL面向本科生和研究生的强有力的外展计划，以及每年向公众开放的开放参观活动。

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5)Detailed information on protein dynamics at an atomic level and its thermodynamic implications is of fundamental biophysical importance for understanding protein stability and function. The overall goal of the project is the development of new methods for a comprehensive description of complex dynamics and thermodynamics of proteins and to demonstrate their applicability to biologically important molecular systems. The recent advent of increasingly long molecular dynamics simulations will be used to close the time-scale gap between simulations and experimental nuclear magnetic resonance (NMR) parameters, in particular residual dipolar couplings and rotating frame relaxation rates. Very long simulations into the ms range will be performed to make quantitative comparisons with experiment both for the protein backbone and the side chains. This information, on the one hand, will yield a comprehensive assessment of the accuracy of molecular mechanics force fields and guide their further optimization. On the other hand, it provides a realistic microscopic approach to the interpretation of these experimental NMR parameters. These simulations also allow analysis of statistically significant correlated motions between soft degrees of freedom, such as dihedral angles, and thereby permit the accurate extraction of configurational entropies. These concepts will be tested on model protein systems and applied to the experimental and computational analysis of the entropy transfer mechanism of the protein MDM2 when it interacts with inhibitors. The results of this research will produce new computational, statistical thermodynamic, and NMR spectroscopic concepts for the characterization of proteins, which will enhance the understanding of protein behavior and function and serve as input for the engineering of proteins with new properties. The results will be disseminated in form of publications and will be made available to the biophysics and biomolecular NMR communities in terms of public web servers. The project provides interdisciplinary training and research opportunities for graduate students at the Department of Chemistry and Biochemistry at Florida State University (FSU), at the Institute of Molecular Biophysics at FSU, and at the National High Magnetic Field Laboratory (NHMFL), which count significant numbers of students from demographically underrepresented groups. Research methods and results will be incorporated into advanced undergraduate and graduate courses on biophysics and biomolecular spectroscopy. The P.I. participates in NHMFL's strong outreach programs for undergraduate and graduate students and at the annual Open House, which is open to the public.