QUANTUM BIOLOGY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 关键词： 分子动力学，经典力学，量子力学，量子与经典耦合势，自由能微扰，平均力势，分而治之，核磁共振 摘要： 在这项提案中，我们要求超级计算机在未来三年内为量子生物学研究提供资金。根据我们的分析，我们在Rachel上每年请求165K节点小时数，在Lemieux上每年请求420K节点小时数。将开展的项目包括：项目1-尿素酶催化机理的理论研究尿素酶的催化机理尚不清楚。1，2为了完成这个项目，我们将进行分子动力学(MD)模拟，以阐明尿素酶活性部位内的质子化模式。3我们还将进行从头计算和密度泛函理论(DFT)计算，研究活性部位的团簇模型，以便详细绘制消除反应路径，并将其与先前关于水解路径的量子力学(QM)工作进行比较。项目2-法尼基转移酶催化机理全景图法尼基转移酶(FTase)是一种锌酶，已通过X射线结晶学、定点突变和动力学实验进行了广泛的研究，试图捕捉其催化能力的本质。一系列晶体结构提供了酶作用每个阶段的快照，这为练习和完善理论工具提供了一个理想的机会。在这里，我们建议对酶反应的每一步，直到限速产物释放步骤，进行MD和QM联合研究。我们的主要目标是生成FTase反应的全景图，并为设计有助于癌症治疗的FTase抑制剂提供指导。项目3-氯酸变位酶催化机理的QM研究本项目将比较从全QM计算得到的结果与具有不同QM区域大小的量子力学/分子力学(QM/MM)模型的结果。分支酸变位酶(CM)体系(6,000个原子)4将用半经验量子化学方法模拟，并计算酶催化Claisen重排的反应路径。计算结果将与半经验QM/MM方法的结果进行比较。这个项目的目标是开始了解QM/MM方法相对于完整的QM方法的局限性，以及对CM催化的洞察。这将作为一个有用的基准，以便更好地理解QM/MM方法的准确性，并将允许更好地为尿素酶和FTase等较大系统设计QM/MM模型，例如，项目4结构模型的核磁共振评分。我们建议探索用QM计算核磁共振(NMR)化学位移的新方法，并将这些方法应用于生物系统的研究。最近，我们开发了一种在半经验MNDO水平上使用分而治之的方法来准确计算核磁共振化学位移的快速方法。这种方法使我们能够利用现有的超级计算机设备来研究几千个原子体系的核磁共振性质，从而解决基本的生物学问题，如预测蛋白质-配体复合体的结构和预测蛋白质的三维结构。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Keywords: Molecular dynamics, classical mechanics, quantum mechanics, coupled quantum and classical potentials, free energy perturbation, potential of mean force, divide and conquer, NMR Abstract: In this proposal we are requesting supercomputer time for the next three years to fund Quantum Biology research. As a result of our analysis we are requesting 165K node hours per year on Rachel and 420K node hours per year on Lemieux. The projects to be pursued include: Project 1-Theoretical Studies of the Urease Catalytic Mechanism The catalytic mechanism of urease is still not well understood. Ongoing research has lead us to postulate that an elimination mechanism can compete with the generally preferred hydrolytic one.1,2 In order to complete this project we will carry out molecular dynamics (MD) simulations to elucidate the protonation pattern within the urease active site.3 We will also carry out ab initio and density functional theory (DFT) calculations to study cluster models of the active site in order to map out the elimination reaction pathway in detail and compare it to previous quantum mechanical (QM) work on the hydrolytic pathway. Project 2- A Panoramic View of the Catalytic Mechanism of Farnesyltransferase Farnesyltransferase (FTase) is a zinc enzyme that has been extensively studied by X-ray crystallography, site-directed mutagenesis, and kinetic experiments, trying to capture the essentials of its catalytic power. A series of crystal structures that provide snapshots of each stage of the enzyme action have been made available, which presents an ideal opportunity for exercising and refining theoretical tools. Here we propose a combined MD, and QM investigation of every step of the enzymatic reaction, up to the rate-limiting product release step. Our primary aim is to generate a panoramic view of the FTase reaction and provide guidance for the design of FTase inhibitors that could aid in the treatment of cancer. Project 3-QM Studies of the Chorismate Mutase Catalytic Mechanism This project will compare results obtained from full QM calculations with those from quantum mechanical/molecular mechanical (QM/MM) models with varying sizes of the QM region. The chorismate mutase (CM) system (6,000 atoms)4 will be modeled with semiempirical QM, and the reaction pathway of the enzyme catalyzed Claisen rearrangement will be calculated. The results will be compared with those derived from semiempirical QM/MM approaches. The goal of this project is to begin to understand the limitations of the QM/MM approach relative to the full QM one as well as providing insight into CM catalysis. This will serve as a useful benchmark in order to better understand the accuracy of QM/MM approaches and will allow for the better design of QM/MM models for bigger systems like urease and FTase, for example, Project 4 Scoring of Structural Models by NMR We propose to explore new approaches to calculate Nuclear Magnetic Resonance (NMR) chemical shifts with QM and to apply these approaches to study biological systems. Recently, we have developed a fast approach to accurately calculate NMR chemical shifts using the divide-and-conquer method at the semiempirical MNDO level. This approach enables us to study NMR properties for systems of several thousands of atoms using current supercomputer facilities and, hence, to tackle fundamental biological problems such as predicting the structure of protein-ligand complexes and the prediction of the 3-D structure of proteins.