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。该项目的总体目标是开发新方法，用于全面描述蛋白质的复杂动力学和热力学，并证明其对生物学重要分子系统的适用性。最近出现的越来越长的分子动力学模拟将被用来关闭模拟和实验核磁共振（NMR）参数，特别是残余偶极耦合和旋转帧弛豫率之间的时间尺度差距。将进行ms范围内的非常长的模拟，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学力场的准确性进行全面评估，并指导其进一步优化。另一方面，它提供了一个现实的微观方法来解释这些实验NMR参数。这些模拟还允许软自由度，如二面角之间的统计上显着的相关运动的分析，从而允许构型熵的准确提取。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MDM 2与抑制剂相互作用时的熵传递机制的实验和计算分析。这项研究的结果将产生新的计算，统计热力学和NMR光谱概念的蛋白质的表征，这将提高蛋白质的行为和功能的理解，并作为输入的蛋白质工程与新的属性。结果将以出版物的形式传播，并通过公共网络服务器提供给生物物理学和生物分子核磁共振社区。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高磁场实验室（NHMFL）的研究生提供了跨学科培训和研究机会，这些研究生中有相当多的学生来自人口统计学上代表性不足的群体。研究方法和结果将纳入高级本科生和研究生课程的生物物理学和生物分子光谱学。私家侦探参加NHMFL为本科生和研究生提供的强大外展计划，并参加向公众开放的年度开放日。

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.