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

项目总结/摘要 近似量子力学计算，特别是密度泛函理论，已经成功地 在过去的几十年里，它被用来帮助理解金属蛋白对各种生物的活性。 对人类和其他生命形式都很重要的基本反应。细胞色素P450 帮助代谢体内的废物，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的困难 含有比这些金属蛋白更小的化合物，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，创造人工版本， 并为它们设计药物靶点。图形上的无相位相干场量子蒙特卡罗方法 处理单元和相关采样提供了传统方法的准确和可扩展的替代方案。 这项应用涉及发展一个本地化的轨道制定这项技术，以推动它从一个 从仅用于小型系统到可靠地用于大型系统。然后，此方法将被用作 更近似的方法的基准，并用作这些金属蛋白的聚类模型的校正。 使用这种方法，关于细胞色素P450的氧化机制，N-N键断裂 固氮酶和血红蛋白的自动氧化以及有关小分子结合的问题 如O2、CO和NO对血红蛋白和肌红蛋白的血红素的反应。这项工作将 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，与哥伦比亚的大卫·赖克曼教授合作， 量子蒙特卡罗。在哥伦比亚的超级计算机设施和在偏远的设施，如橡树岭 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。的 研究金培训计划包括在高影响力期刊上发表文章， 理论化学界和生物化学界。它还包括指导 研究生。职业发展计划包括参加办公室举办的讲习班， 博士后事务以及继续在哥伦比亚大学博士后协会的领导作用。

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.