Quantum Chemical Evaluation of NMR Chemical Shifts in Proteins

该项目的总体目标由分子和细胞生物科学部的分子生物物理学和化学部的计算和理论化学计划共同支持，目的是使用现代量子力学(QM)通过溶剂的连续表示来提供对生物分子系统中核磁共振化学位移的准确和独特的见解。为了实现这一首要目标，PI将继续验证和开发他的基于QM的核磁共振(QM NMR)方法，并将其应用于与生物大分子的结构和动力学有关的生物学问题。具体地说，PI将通过开发一种结合QM/分子力学(MM)的核磁共振方法来扩展QM核磁共振方法的计算效率，该方法将把计算工作集中在感兴趣的区域。他将把QM核磁共振方法可以处理的原子核扩展到19F，以便可以进行19F研究，以研究生物系统的结构和动力学。利用QM核磁共振方法，PI开发了一种名为NMRScore的方法，以表明他可以使用以化学位移微扰(CSPs)形式的核磁共振化学位移信息来仅基于配体CSPs对蛋白质口袋中的小分子位置进行“评分”。除了验证NMRScore，PI还将测试基于QM/MM的NMRScore，以验证其有效性，并展示其优于完全基于QM的NMRScore协议的计算性能。最后，PI将使用QM核磁共振对正确的蛋白质折叠和错误的蛋白质折叠进行“评分”，并展示其作为结构验证工具的能力。这个项目的智力价值是开发和应用高度复杂的量子力学工具来检查生物系统中的核磁共振化学位移。这种方法过去没有被采用，因为对于具有1000‘S原子的系统，基于QM的方法的费用很高，但随着最近算法和计算机硬件的进步，现在人们可以用完全的QM模型来处理生物系统。结构生物学家还产生了大量数据，可用于验证研究生物分子中核磁共振化学位移的QM方法。该项目将对学生进行形式化理论、计算机编程以及生物结构和功能方面的培训。这项培训将为他们在公共或私营部门工作做好准备。私家侦探将把他的代码分发给有关各方

The overall goal of this project, jointly supported by Molecular Biophysics in the Division of Molecular and Cellular Biosciences and the Computational and Theoretical Chemistry Program in the Chemistry Division, is to use modern quantum mechanics (QM) to provide accurate and unique insights into NMR chemical shifts in biomolecular systems using a continuum representation for the solvent. To reach this overarching goal, the PI will continue to validate and develop his QM based NMR (QM NMR) approach and apply it to biologically relevant problems regarding the structure and dynamics of biomacromolecules. Specifically, the PI will extend the computational efficiency of the QM NMR methodology through the development of a combined QM/molecular mechanics (MM) NMR approach, which will focus the computational effort on the region of interest. He will extend the nuclei that the QM NMR approach can handle to 19F, in order that 19F studies can be carried out to study the structure and dynamics of biological systems. Using the QM NMR approach, the PI developed a method called NMRScore to indicate the fact that he can use NMR chemical shift information in the form of chemical shift perturbations (CSPs) to "score" the position of a small molecule in a protein pocket based on ligand CSPs only. Along with validating NMRScore, the PI will also test a QM/MM based NMRScore in order to validate its efficacy and to demonstrate its superior computational performance over a fully QM based NMRScore protocol. Finally, the PI will use QM NMR to "score" correct versus incorrect protein folds and to also demonstrate its capabilities as a structure validation tool. The intellectual merit of this project is to develop and apply highly sophisticated quantum mechanical tools for the examination of NMR chemical shifts in biological systems. This approach has not been adopted in the past because of the expense of QM based methodologies for systems with 1000's of atoms, but with recent algorithmic and computer hardware advances, one can now tackle biological systems with fully QM models. Structural biologists have also generated an immense amount of data that can be used to validate QM approaches to the study of NMR chemical shifts in biomolecules. This project will train students in formal theory, computer programming, and biological structure and function. This training will prepare them for jobs in either the public or private sector. The PI will distribute his codes to interested parties