Understanding electronically non-adiabatic reactions in biomolecules with multiscale simulations

通过多尺度模拟了解生物分子中的电子非绝热反应

• 批准号: 10714663
• 负责人: Ruibin Liang
• 金额: $ 36万
• 依托单位: TEXAS TECH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-05 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714663
• 关键词: Biochemical Reaction; Biology; Biomedical Research; Chemicals; Circadian Rhythms; Complex; Computing Methodologies; Electron Transport; Electronics; Electrons; Energy Metabolism; Environment; Enzymes; Event; Future; Laboratories; Light; Metabotropic Glutamate Receptors; Methodology; Methods; Microscopic; Molecular; Motion; Nature; Nuclear; Organism; PUVA Photochemotherapy; Pathway interactions; Pharmaceutical Preparations; Process; Protein Conformation; Proteins; Quantum Mechanics; Reaction; Research; Risk; Role; Sampling; Science; Signal Transduction; System; TRP channel; Techniques; chemical kinetics; chemical reaction; chemotherapy; circadian pacemaker; computerized tools; cost; cryptochrome; design; human subject; insight; interest; magnetic field; molecular mechanics; next generation; optogenetics; programs; protein structure; quantum; rational design; response; side effect; simulation

The Liang laboratory uses molecular simulations to fundamentally understand how electronically non- adiabatic reactions couple with protein’s structure, dynamics, and function. Electronically non-adiabatic reactions, such as photochemical and electron transfer reactions, switch electronic states during the chemical transformation. A fundamental understanding of how they interact with proteins is essential for advances in biomedical sciences. However, two central and fundamental questions remain elusive: (1) how does the protein environment modulate the pathway, dynamics, and quantum yields of the non-adiabatic reactions? (2) how do the non-adiabatic reactions induce structural changes in the protein? Molecular simulation is indispensable to answering these questions because it can resolve the energetics and kinetics of chemical reactions at atomic- level detail, which is often beyond the limit of current experimental techniques. Also, simulation incurs minimal cost and has no risk for human subjects. However, the multiscale nature of these processes poses significant challenges for traditional computational methods. Specifically, standard molecular mechanics (MM) simulations cannot describe the quantum-mechanical (QM) nature of the non-adiabatic reactions. Meanwhile, typical QM simulations are too expensive to characterize the slow biomolecular motions in response to these reactions. To overcome these challenges, in the next five years, our research program will expand our current efforts to develop and employ multiscale simulation methods to understand (1) the light-regulated signaling activities of transient receptor potential channels and metabotropic glutamate receptors by synthetic molecular switches, which are of top interest in optogenetics and photopharmacology, and (2) the long-range electron transfer events in cryptochromes and electron bifurcating enzymes, which are fundamental to understanding the circadian clocks, magnetic field sensing and energy metabolism in living organisms. The unique advantages of our approaches include (1) accurate and efficient non-adiabatic dynamics simulations with “on-the-fly” ab initio calculations of nuclear gradients and electronic couplings; (2) effective integration of the high-quality non-adiabatic dynamics simulations with high-efficiency MM sampling of protein conformational change. These key methodological advantages will enable the comprehensive characterization of non-adiabatic chemical reactivity in complex biomolecular systems and answer the above-mentioned fundamental questions with unprecedented accuracy. Explicitly simulating the photodynamics of biomolecules of this size and complexity is not routine, especially with the proposed multiscale simulation framework that incorporates ab initio non-adiabatic dynamics simulations. Therefore, five years into the future, our research will provide new insights into the design principles of next- generation photochemotherapy with minimal side effects, create powerful computational tools for simulating electron transfer in biomolecules, and deepen our fundamental understanding of the roles of quantum mechanics in biology in general.

梁实验室使用分子模拟从根本上了解电子非 - 绝热反应夫妇与蛋白质的结构，动力学和功能。电子非绝热反应， 例如光化学和电子传输反应，在化学期间切换电子状态 转型。对它们如何与蛋白质相互作用的基本了解对于进步至关重要 生物医学科学。但是，两个中心和基本问题仍然难以捉摸：（1）蛋白质如何 环境调节非绝热反应的途径，动力学和量子产量？ （2）如何 非绝热反应会引起蛋白质的结构变化？分子模拟是必不可少的 回答这些问题，因为它可以解决原子化的化学反应的能量和动力学 水平细节通常超出当前实验技术的极限。另外，模拟会导致最小 成本，没有人类受试者的风险。但是，这些过程的多尺度具有重要的 传统计算方法的挑战。具体而言，标准分子力学（MM）模拟 无法描述非绝热反应的量子力学（QM）性质。平均典型QM 模拟太昂贵了，无法响应这些反应来表征缓慢的生物分子运动。 为了克服这些挑战，在接下来的五年中，我们的研究计划将扩大我们目前的努力 开发和员工多尺度模拟方法以了解（1） 通过合成分子开关，瞬态受体电势通道和代谢型谷氨酸受体， 这是光遗传学和光肢体学的最高兴趣，以及（2）远程电子转移事件 在隐性和电子分叉酶中，这对于理解昼夜节律的基础是 磁场灵敏度和活性生物中的能量代谢。我们方法的独特优势 包括（1）具有“直接”从头算的准确而有效的非绝热动态模拟 核梯度和电子耦合； （2）高质量非绝热动态的有效整合 蛋白质构象变化的高效MM采样模拟。这些关键的方法论 优势将使复合物中非绝热化学反应的全面表征 生物分子系统并以前所未有的准确性回答上述基本问题。 明确模拟这种大小和复杂性的生物分子的光学不是常规的，尤其是 提出的多尺度模拟框架结合了非绝热动力学模拟。 因此，未来五年，我们的研究将为下一步的设计原则提供新的见解。 具有最小副作用的生成光化学疗法，创建强大的计算工具用于模拟 生物分子中的电子转移，并加深我们对量子力学作用的基本理解 一般来说生物学。