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门的分子生物物理学和化学部门的计算和理论化学计划共同支持，是使用现代量子力学（QM）提供准确和独特的见解，使用溶剂的连续表示在生物分子系统中进行NMR化学位移。为了实现这一总体目标，PI将继续验证和开发他的基于QM的NMR（QM NMR）方法，并将其应用于有关生物大分子结构和动力学的生物相关问题。 具体而言，PI将通过开发组合QM/分子力学（MM）NMR方法来扩展QM NMR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。 他将扩展QM NMR方法可以处理的核到19 F，以便可以进行19 F研究来研究生物系统的结构和动力学。使用QM NMR方法，PI开发了一种名为NMRScore的方法，以表明他可以使用化学位移扰动（CSP）形式的NMR化学位移信息来“评分”仅基于配体CSP的蛋白质口袋中小分子的位置。沿着验证NMRScore，PI还将测试基于QM/MM的NMRScore，以验证其有效性，并证明其上级计算性能优于完全基于QM的NMRScore方案。最后，PI将使用QM NMR对正确与不正确的蛋白质折叠进行“评分”，并证明其作为结构验证工具的能力。该项目的智力价值是开发和应用高度复杂的量子力学工具，用于检查生物系统中的NMR化学位移。这种方法在过去没有被采用，因为基于QM的方法用于具有1000个原子的系统的费用，但是随着最近的算法和计算机硬件的进步，现在可以用完全QM模型来处理生物系统。结构生物学家还产生了大量的数据，可用于验证QM方法来研究生物分子的NMR化学位移。本计画将训练学生形式理论、电脑程式设计、生物结构与功能。这种培训将使他们为在公共或私营部门工作做好准备。 PI将把他的代码分发给感兴趣的各方

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