Dynamics, Structure, and Function of Proteins by NMR and Computation

生命系统的关键功能，如人类、动物、微生物和植物，在微观层面上通常是由大的生物分子来完成的，其中包括许多不同类型的蛋白质。大多数蛋白质采用多种形状（构象），不断地相互转化。这些构象及其寿命之间的平衡使蛋白质能够获得执行各种重要生物功能所必需的特性。这包括对形成分子复合物的大分子和小分子的特定识别，包括与药物的相互作用，化学反应的加速，以及生命系统必不可少的许多其他相互作用。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CCIC核磁共振中心将被用来向更广泛的公众介绍基础和应用分子研究的发现和好处。高中生将有机会对自己的样品进行核磁共振实验和分析。将组织核磁共振研讨会，介绍和培训来自俄亥俄州学术界和工业界的未来核磁共振用户。在原子细节上描绘蛋白质的结构和动力学的构象集合的现实表示具有基本的生物物理学重要性，因为它提供了对蛋白质特性和功能的更好理解，例如稳定性，分子相互作用，识别，协同性和变构。在这个项目中，将开发新的和广泛适用的方法，通过将核磁共振（NMR）光谱与先进的计算机模拟相结合，并将这些方法应用于各种分子系统，来全面描述球形和内在无序蛋白（IDP）的构象动力学。这包括研究钠钙交换剂NCX通过其大细胞质环的变构调节以及不同IDPs与合成纳米颗粒的相互作用模式。在皮秒到纳秒和毫秒时间尺度上快速同时筛选蛋白质侧链动力学的新方法将被开发并应用于生物学上重要的蛋白质系统。在蛋白质环中观察到的非均相动力学行为将为分子动力学力场的系统改进提供依据。这项研究将产生新的实验、网络服务器和软件，以便更准确、更真实地描述蛋白质在其原生环境中的特征以及它们与纳米颗粒的相互作用。核磁共振波谱与高性能计算的结合有望应用于广泛的生物分子系统。这些工具将提供给结构生物学、生物物理学和生物分子核磁共振社区。它们的应用将增强对蛋白质行为和功能的理解，并为具有新特性的蛋白质工程和更好的药物设计提供输入。

Critical functions of living systems, such as humans, animals, microbes, and plants, at the microscopic level are often carried out by large biological molecules, which include many different types of proteins. Most proteins adopt multiple shapes (conformations) that incessantly interconvert into each other. The balance between these conformations and their life spans allows proteins to attain properties that are necessary to perform a variety of important biological functions. This includes the specific recognition of large and small molecules for the formation of molecular complexes, including interactions with drugs, the acceleration of chemical reactions, and many other interactions essential for living systems. The project aims at a deeper understanding of these fundamental processes, which will assist the development 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 CCIC NMR center will be utilized to introduce a broader public to the discoveries and benefits of basic and applied molecular research. High-school students will have the opportunity to perform and analyze NMR experiments of their own samples. NMR workshops will be organized to introduce and train future NMR users from academia and industries in Ohio. The realistic representation of conformational ensembles of proteins depicting both structure and dynamics at atomistic detail is of fundamental biophysical importance as it provides a better understanding of protein properties and function, such as stability, molecular interactions, recognition, cooperativity, and allostery. During this project, new and broadly applicable methods will be developed for a comprehensive description of the conformational dynamics of globular and intrinsically disordered proteins (IDP) by combining nuclear magnetic resonance (NMR) spectroscopy with advanced computer simulations, and applying these methods to a variety of molecular systems. This includes studies of the allosteric regulation of the sodium-calcium exchanger NCX via its large cytoplasmic loop and the interaction modes of different IDPs with synthetic nanoparticles. New methods for the rapid and simultaneous screening of protein side-chain dynamics on the picosecond-to-nanosecond timescale and the millisecond timescale will be developed and applied to biologically important protein systems. Heterogeneous dynamics behavior observed in protein loops will serve for the systematic improvement of molecular dynamics force fields. The research will produce new experiments, web servers, and software for the more accurate and realistic characterization of proteins in their native environment and their interaction with nanoparticles. The combination of NMR spectroscopy with high-performance computation is expected to become applicable to a wide range of biomolecular systems. These tools will be made available to the structural biology, biophysics, and biomolecular NMR communities. Their application will enhance the understanding of protein behavior and function and serve as input for the engineering of proteins with new properties and the design of better drugs.