Accurate Quantum Chemistry of Protein Active Sites using Auxiliary-Field Quantum Monte Carlo

使用辅助场量子蒙特卡罗对蛋白质活性位点进行精确的量子化学分析

• 批准号: 9911383
• 负责人: Benjamin Rudshteyn
• 金额: $ 6.49万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911383
• 关键词: Active Sites; Benchmarking; Binding; Biochemistry; Carbon Monoxide; Cardiovascular system; Chemicals; Chemistry; Collaborations; Communities; Cytochrome P450; Development; Development Plans; Devices; Disputes; Dissociation; Drug Design; Drug Targeting; Educational workshop; Fellowship; Food; Food production; Formulation; Growth; Health; Heme; Hemoglobin; Human; Iron; Journals; Leadership; Life; Ligand Binding; Mechanics; Memory; Mentors; Mentorship; Metabolism; Metalloproteins; Methods; Modeling; Myoglobin; Nitric Oxide; Nitrogen; Nitrogenase; Outcome; Oxygen; Protein Chemistry; Proteins; Publishing; Reaction; Resources; Role; Running; Sampling; Societies; Speed; Supercomputing; System; Techniques; Training; Transition Elements; Universities; Waste Products; Work; base; career development; density; design; graduate student; improved; novel therapeutics; oxidation; prevent; protonation; quantum; quantum chemistry; small molecule; symposium; theories

Project Summary/Abstract Approximate quantum mechanical calculations, particularly density functional theory, have been successfully used in the previous few decades to help understand the activity of metalloproteins towards various fundamental reactions important both to humans and other forms of life. Examples include Cytochrome P450 which helps metabolize waste products in the body, nitrogenase which takes part in the nitrogen cycle important for food growth, and hemoglobin and myoglobin which regulate oxygen and nitric oxide transport in the body. However, these theoretical methods often have serious difficulty in the treatment of transition metal containing compounds even smaller than these metalloproteins, making interpretation of mechanism in these systems uncertain. This difficulty, in turn makes it difficult to redesign these proteins, create artificial versions, and to design drug targets for them. Phaseless auxiliary-field quantum Monte Carlo (ph-AFQMC) on graphical processing units and correlated sampling offers an accurate and scalable alternative to traditional methods. This application involves the development of a localized orbital formulation of this technique to push it from one only used on small systems to one used reliably on large systems. Then this method will be used both as a benchmark for more approximate methods and used as a correction to cluster models of these metalloproteins. Using this method, questions regarding the mechanism of oxidation in Cytochrome P450, N-N bond cleavage in nitrogenase, and autoxidation in hemoglobin as well as questions regarding the binding of small molecules such as O2, CO, and NO to the heme of hemoglobin and myoglobin will be answered. The work will be undertaken at Columbia University under the mentorship of Prof. Richard Friesner in the chemistry department, an expert in metalloprotein modeling, in collaboration with Prof. David Reichman at Columbia, an expert in Quantum Monte Carlo. The supercomputing facilities at Columbia and at remote facilities such as Oak Ridge National Lab Leading Computing Facility and NSF XSEDE include ample CPU and GPU resources. The fellowship training plan involves publishing in high impact journals and presenting at conferences for both the theoretical chemistry community and the biochemistry community. It also includes the opportunity to mentor graduate students. The career development plans includes attending workshops organized by the Office of Postdoctoral Affairs as well continuing in a leadership role in the Columbia University Postdoctoral Society.

项目概要/摘要 近似量子力学计算，特别是密度泛函理论，已经成功 在过去的几十年中用于帮助了解金属蛋白对各种 对人类和其他生命形式都很重要的基本反应。例子包括细胞色素 P450 帮助代谢体内废物，固氮酶参与氮循环 对食物生长很重要，血红蛋白和肌红蛋白调节氧气和一氧化氮的运输 身体。然而，这些理论方法在处理过渡金属时往往存在严重困难。 含有比这些金属蛋白更小的化合物，从而解释了这些金属蛋白的机制 系统不确定。这种困难反过来又使得重新设计这些蛋白质、创建人工版本变得困难， 并为其设计药物靶点。图形上的无相辅助场量子蒙特卡罗 (ph-AFQMC) 处理单元和相关采样为传统方法提供了准确且可扩展的替代方案。 该应用涉及开发该技术的局部轨道公式，以将其从一个 仅在小型系统上使用到在大型系统上可靠使用的一种。那么这个方法将被用作 更近似方法的基准，并用作这些金属蛋白聚类模型的校正。 使用这种方法，关于细胞色素 P450 氧化机制、N-N 键断裂的问题 固氮酶、血红蛋白的自氧化以及有关小分子结合的问题 血红蛋白和肌红蛋白的血红素如O2、CO、NO等都会得到解答。这项工作将是 在哥伦比亚大学化学系 Richard Friesner 教授的指导下进行， 金属蛋白建模专家，与哥伦比亚大学 David Reichman 教授合作，该教授是金属蛋白建模专家 量子蒙特卡罗。哥伦比亚大学和橡树岭等远程设施的超级计算设施 国家实验室领先的计算设施和 NSF XSEDE 包括充足的 CPU 和 GPU 资源。这 研究金培训计划包括在高影响力期刊上发表文章并在会议上发表演讲 理论化学界和生物化学界。它还包括指导的机会 研究生。职业发展计划包括参加办公室组织的研讨会 博士后事务并继续在哥伦比亚大学博士后协会担任领导职务。