Structural Dynamics and Function of Proteins by NMR and Computation

蛋白质是分子机器，在人体中起着重要的生物作用。在这个项目中，将开发新的实验和计算方法，将分子生物物理学与纳米科学结合起来，观察蛋白质在时间尺度上的运动，这是以前无法达到的，以帮助破译分子运动在蛋白质功能中的作用，以及蛋白质-配体和蛋白质-蛋白质复合物的形成。实验方法将使用由多维核磁共振波谱（NMR）和分子动力学（MD）计算机模拟测量的位点特异性弛豫特性。该项目旨在更深入地了解这些基本过程，这将有助于开发新的治疗方法和具有新特性的蛋白质工程。该项目为俄亥俄州立大学的本科生、研究生和博士后提供跨学科的培训和研究机会，为来自人口统计学上代表性不足的群体的大量学生提供服务。新的国家门户超高场核磁共振中心将提供机会向更广泛的公众介绍基础和应用分子研究的发现和好处。Title 1来自该地区的高中生将访问并对他们在课堂上合成的样品进行NMR实验和分析。将组织会议和研讨会，培训来自俄亥俄州、中西部地区和全国各地学术界和工业界的当前和未来的NMR用户。在原子细节上对蛋白质结构和动力学的真实表征对于理解蛋白质的功能至关重要。蛋白质动力学可以发生在飞秒到毫秒甚至更远的时间尺度范围内，但连接纳秒和微秒动力学的时间尺度制度已经明显难以通过实验获得。纳米粒子辅助核磁共振自旋弛豫（NASR）有望在纳秒到微秒的原子分辨率时间尺度上精确和全面地测量蛋白质动力学。它将被开发并应用于一系列具有不同生物物理性质和功能的蛋白质，包括主链和侧链，为这些未知时间尺度上的蛋白质动力学行为提供新的见解。新的数据以及实验数据库信息也将用于MD力场的验证和系统改进，这是越来越现实的高性能计算的基础，用于蛋白质性质和功能的计算机预测，包括蛋白质-蛋白质和蛋白质-配体相互作用，变构和生物分子运输。新的光谱采样和自动化分析工具将用于非常快速和常规测量广泛使用的蛋白质动力学参数，这将有助于阐明蛋白质结构动力学与功能之间的复杂关系，用于筛选应用。该项目由分子和细胞生物科学部的分子生物物理集群资助。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Proteins are molecular machines that play a critical biological role in the human body. In this project, new experimental and computational methods will be developed that combine molecular biophysics with nanoscience to observe motions of proteins on timescales that were previously inaccessible to help decipher the role of molecular motion in protein function and the formation of protein-ligand and protein-protein complexes. The experimental approaches will use site-specific relaxation properties measured by multidimensional nuclear magnetic resonance spectroscopy (NMR) accompanied by molecular dynamics (MD) computer simulations. The project aims at a deeper understanding of these fundamental processes, which will assist the development of new cures and the engineering of proteins with new properties. This project provides interdisciplinary training and research opportunities for undergraduate students, graduate students, and postdocs at Ohio State in programs that serve significant numbers of students from demographically underrepresented groups. The new National Gateway Ultrahigh Field NMR Center will offer opportunities to introduce a broader public to the discoveries and benefits of basic and applied molecular research. Title 1 high school students from the area will visit to perform and analyze NMR experiments of samples they synthesized in class. Conferences and workshops will be organized to train current and future NMR users from academia and industries in Ohio, the Midwestern region, and from across the nation. The realistic representation of protein structure and dynamics at atomic detail is essential for understanding protein function. Protein dynamics can occur on a wide range of timescales covering femtoseconds to milliseconds and even beyond, but the timescale regime bridging nanosecond and microsecond dynamics has been notably difficult to access by experiments. Nanoparticle-assisted NMR spin relaxation (NASR) promises the accurate and comprehensive measurement of protein dynamics on nanosecond to microsecond timescales at atomic resolution. It will be developed and applied to a range of proteins with different biophysical properties and function both for the backbone and the side chains providing novel insights on protein dynamics behavior on these unchartered timescales. The new data, along with experimental database information, will also be used for the validation and systematic improvement of MD force fields, which underlie increasingly realistic high-performance computations for the in-silico prediction of protein properties and function, including protein-protein and protein-ligand interactions, allostery, and biomolecular transport. New spectral sampling and automated analysis tools will be developed for the very rapid and routine measurement of widely used protein dynamics parameters, which will help elucidate the intricate relationship between protein structural dynamics and function for screening applications. This project is funded by the Molecular Biophysics Cluster in the Division of Molecular and Cellular Biosciences.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.