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.

项目摘要/摘要 近似量子机械计算，尤其是密度功能理论，已成功 在过去的几十年中，用于了解金属蛋白对各种的活性 基本反应对人类和其他形式的生活都很重要。例子包括细胞色素P450 这有助于代谢体内的废物，氮酶参与氮循环 对于食物生长以及调节氧气和一氧化氮转运的血红蛋白和肌球蛋白很重要 身体。但是，这些理论方法在过渡金属的处理中通常会严重困难 含有比这些金属蛋白更小的化合物，在这些中解释机制 系统不确定。这种困难又使得很难重新设计这些蛋白质，创建人造版本， 并为他们设计药物目标。图形上无用的辅助场量子蒙特卡洛（pH-afqmc） 处理单元和相关的采样提供了传统方法的准确替代方案。 此应用涉及开发该技术的局部轨道配方 仅在小型系统上可靠地用于大型系统。然后，该方法将两者都用作 基准用于更近似方法，并用作对这些金属蛋白的聚类模型的校正。 使用这种方法，有关细胞色素P450，N-N键裂解中氧化机制的问题 在氮酶和血红蛋白中的自氧化以及有关小分子结合的问题 例如O2，CO，以及对血红蛋白和肌红蛋白的血红素的NO。工作将是 在化学系理查德·弗里斯纳（Richard Friesner）教授的指导下，在哥伦比亚大学进行 金属蛋白建模专家，与哥伦比亚的David Reichman教授合作，专家 量子蒙特卡洛。哥伦比亚的超级计算设施以及橡树岭等偏远设施 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 奖学金培训计划涉及在高影响期刊上发布，并在会议上展示 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由 博士后事务以及在哥伦比亚大学博士后学会中扮演领导角色。