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.

项目摘要/摘要 对生物过程的基本理解对于进一步发展是必要的 将受益于人类健康的治疗和技术。原则上，量子力学定律 掌握这种理解的钥匙，并有可能揭示（可能的最高分辨率） 生物系统中自然发生的生理过程的每个细节以及相关机制 可以利用以打击疾病并改善健康的行动。在实践中，尽管很快 进步，调查量子现象的最先进方法仍然相当有限，因为 实验技术面临解决方案和解释性歧义的困难，而精确的理论 预测需要计算工作，这会随着系统大小而成倍增长。该建议旨在 利用并进一步开发有希望的计算方法，将与实验一起使用 技术，为质子耦合电子传输（PCET）过程提供前所未有的见解和 生物学中自然发生的过渡金属的催化能力。第一个提出的研究目的 涉及二维电子振动光谱和激发态电子的组合 结构计算以探测仿生，合成模型化合物中的超快PCET动力学 光系统II。这项工作将产生有关人类无处不在的PCET图案的一般见解 生物学，并且在肌萎缩性侧索硬化症等疾病中起关键作用。第二个目标 将开发有效的计算方案，以准确预测潜在药物的结合亲和力 候选者进入包含过渡金属离子的蛋白质位点。这项技术将几乎翻一番 可以通过合理的药物设计平台解决的可药物目标数量，并将加速 发现广泛的新疗法。第三项研究目的旨在调查 金属配合物具有非一般配体的多重电子结构，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，并建模 包含铁和硫原子的多金属系统的氧化还原活性。这项研究将进行 在马丁·盖登（Martin Head-Gordon）担任赞助商和格雷厄姆·弗莱明（Graham Fleming）的指导下，两位教授 加州大学伯克利分校（UCB）化学。拟议的培训计划将利用 UCB的专业知识和刺激环境的多样性，实验室中存在协同作用， 部门和附属机构。职业发展计划涉及指导的机会 研究生，并发展教学，公开演讲和赠款技巧，这将帮助我 实现成为研究小组领导者的目标，加入了所有人的科学家社区 解决将导致健康改善的紧迫问题的背景。

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