Towards a quantum-mechanical understanding of proton-coupled electron transfer and transition metal reactivity in biological processes

对生物过程中质子耦合电子转移和过渡金属反应性的量子力学理解

• 批准号: 10386836
• 负责人: James Shee
• 金额: $ 6.76万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10386836
• 关键词: ATP Synthesis Pathway; Affinity; Amyotrophic Lateral Sclerosis; Binding; Biological; Biological Process; Biology; Biomimetics; California; Catalysis; Charge; Chemicals; Chemistry; Communities; Complement; Complex; Computational Technique; Computer Models; Computing Methodologies; Coupled; Creativeness; Cytochrome P450; DNA Repair; Data Set; Development; Disease; Docking; Drug Design; Drug Targeting; Educational process of instructing; Electron Transport; Entropy; Environment; Enzymes; Event; Exhibits; Face; Ferredoxin; Free Energy; Goals; Grant; Half-Life; Head; Health; Heme; Histidine; Human; Human Biology; Institution; Investigation; Ions; Iron; Knowledge; Laws; Lead; Ligands; Magnetism; Measurement; Mechanics; Mentors; Metabolism; Metals; Methodology; Methods; Mitochondrial Myopathies; Modeling; Molecular; Molecular Conformation; Nature; Outcome; Oxidation-Reduction; Pharmaceutical Preparations; Photosynthesis; Physiological Processes; Play; Porphyrins; Positioning Attribute; Process; Property; Proteins; Protocols documentation; Protons; Public Speaking; Quantum Mechanics; Research; Resolution; Resources; Respiration; Role; Scientist; Site; Solvents; Spectrum Analysis; Sulfur; System; Techniques; Technology; Temperature; Therapeutic; Thermodynamics; Time; Training; Transition Elements; Tyrosine; United States National Institutes of Health; Universities; Work; Writing; base; biological systems; career development; combat; density; drug candidate; drug metabolism; druggable target; electronic structure; experimental study; flexibility; graduate student; improved; insight; metal complex; novel therapeutics; oxygen transport; perturbation theory; photosystem II; professor; quantum; rational design; simulation; skills; success; synergism; theories; tool; two-dimensional; vibration

Project Summary/Abstract A fundamental understanding of biological processes is necessary to further the advancement of therapeutics and technologies that will benefit human health. In principle, the laws of quantum mechanics hold the key to such an understanding, with the potential to reveal (with the highest resolution possible) every detail of physiological processes that occur naturally in biological systems, and relevant mechanisms of action that can be harnessed to combat disease and improve health. In practice, however, despite rapid advances, state-of-the-art methodologies for investigating quantum phenomena are still rather limited, as experimental techniques face difficulties of resolution and interpretive ambiguities while exact theoretical predictions require computational effort which grows exponentially with system size. This proposal aims to utilize and further develop promising computational methods, to be used in concert with experimental techniques, to provide unprecedented insights into proton-coupled electron transfer (PCET) processes and the catalytic ability of transition metals that occur naturally in biology. The first proposed research aim involves the combination of two-dimensional electronic vibrational spectroscopy and excited-state electronic structure calculations to probe the ultrafast PCET dynamics in a biomimetic, synthetic model compound of Photosystem II. This work will yield general insights regarding the PCET motif which is ubiquitous in human biology, and which plays a critical role in diseases such as Amyotrophic Lateral Sclerosis. The second aim will develop an efficient computational protocol to accurately predict the binding affinity of potential drug candidates into protein sites that contain transition metal ions. This technology will nearly double the number of druggable targets that can be tackled with rational drug design platforms, and will accelerate the discovery of a wide range of new therapeutics. The third research aim seeks to investigate the multireference electronic structure of metal complexes with non-innocent ligands, in particular the motif of heme binding to O2 as found in oxygen transport and the catalytic cycle of cytochrome P450, and to model the redox activity of multi-metal systems containing iron and sulfur atoms. This research will be performed with the guidance of Martin Head-Gordon as sponsor and Graham Fleming as collaborator, both Professors of Chemistry at University of California, Berkeley (UCB). The proposed training plan will take advantage of the diversity of expertise and stimulating environment at UCB, with synergies present across labs, departments, and affiliated institutions. The plan for career development involves the opportunity to mentor graduate students, and to develop teaching, public speaking, and grant-writing skills that will help me to achieve the goal of becoming a leader of a research group, joining a community of scientists from all backgrounds to solve pressing problems that will lead to the improvement of health.

项目总结/摘要 对生物过程的基本理解是进一步推进生物学的必要条件。 有益于人类健康的治疗方法和技术。原则上，量子力学定律 掌握着这种理解的关键，有可能揭示（尽可能高的分辨率） 生物系统中自然发生的生理过程的每一个细节，以及相关机制 可以用来对抗疾病和改善健康。然而，在实践中，尽管快速 尽管量子力学的发展取得了一些进展，但研究量子现象的最先进的方法仍然相当有限， 实验技术面临着分辨率和解释模糊的困难，而精确的理论 预测需要计算工作量，该计算工作量随着系统规模呈指数增长。这项建议旨在 利用并进一步发展有前途的计算方法，与实验相结合， 技术，以提供前所未有的见解质子耦合电子转移（PCET）过程， 生物体中自然存在的过渡金属的催化能力。第一次提出研究目标 包括二维电子振动光谱和激发态电子 结构计算探测超快PCET动力学的仿生，合成模型化合物的 光系统II。这项工作将产生关于PCET基序的一般见解，这是普遍存在于人类 它在肌萎缩性侧索硬化症等疾病中起着关键作用。第二个目的 将开发一种有效的计算方案，以准确预测潜在药物的结合亲和力， 候选人进入含有过渡金属离子的蛋白质位点。这项技术将使 一些可通过合理的药物设计平台解决的药物目标，并将加速 发现了一系列新的治疗方法。第三个研究目标是调查 具有非无辜配体的金属配合物的多参考电子结构，特别是 血红素与O2结合，如在氧转运和细胞色素P450的催化循环中发现的，并建立模型 含有铁和硫原子的多金属体系的氧化还原活性。这项研究将在 在马丁·海德·戈登（Martin Head Gordon）作为赞助商和格雷厄姆·弗莱明（Graham Fleming）作为合作者的指导下，两位教授 他是加州大学伯克利分校（UCB）的化学教授。拟议的培训计划将利用 UCB专业知识的多样性和令人兴奋的环境，以及实验室之间的协同效应， 部门和附属机构。职业发展计划包括指导的机会 研究生，并发展教学，公开演讲，和赠款写作技巧，这将有助于我 实现成为一个研究小组的领导者的目标，加入一个来自所有科学家的社区， 背景来解决紧迫的问题，从而改善健康。

项目成果

Concerted Electron-Nuclear Motion in Proton-Coupled Electron Transfer-Driven Grotthuss-Type Proton Translocation.

• DOI: 10.1021/acs.jpclett.2c00585
• 发表时间: 2022-05-26
• 期刊: JOURNAL OF PHYSICAL CHEMISTRY LETTERS
• 影响因子: 5.7
• 作者: Arsenault, Eric A.;Guerra, Walter D.;Shee, James;Cruz, Edgar A. Reyez;Yoneda, Yusuke;Wadsworth, Brian L.;Odella, Emmanuel;Urrutia, Maria N.;Kodis, Gerdenis;Moore, Gary F.;Head-Gordon, Martin;Moore, Ana L.;Moore, Thomas A.;Fleming, Graham R.
• 通讯作者: Fleming, Graham R.

Bridging physical intuition and hardware efficiency for correlated electronic states: the local unitary cluster Jastrow ansatz for electronic structure.

• DOI: 10.1039/d3sc02516k
• 发表时间: 2023-10-18
• 期刊: CHEMICAL SCIENCE
• 影响因子: 8.4
• 作者: Motta, Mario;Sung, Kevin J.;Whaley, K. Birgitta;Head-Gordon, Martin;Shee, James
• 通讯作者: Shee, James

Caught in the act: real-time observation of the solvent response that promotes excited-state proton transfer in pyranine.

• DOI: 10.1039/d2sc07126f
• 发表时间: 2023-04-12
• 期刊: Chemical science
• 影响因子: 8.4