Understanding electronically non-adiabatic reactions in biomolecules with multiscale simulations

梁实验室利用分子模拟从根本上理解电子非 绝热反应与蛋白质的结构、动力学和功能耦合。电子非绝热反应， 例如光化学和电子转移反应，在化学过程中切换电子状态 转变。对它们如何与蛋白质相互作用的基本了解对于科学进步至关重要 生物医学科学。然而，两个核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路径、动力学和量子产率？ (2)怎么做 非绝热反应会引起蛋白质的结构变化吗？分子模拟不可或缺 回答这些问题是因为它可以解决原子化学反应的能量学和动力学问题 级别细节，这通常超出了当前实验技术的限制。此外，模拟所产生的影响最小 成本并且对人类受试者没有风险。然而，这些过程的多尺度性质带来了显着的影响 传统计算方法面临的挑战。具体来说，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。同时，典型的 QM 模拟成本太高，无法表征响应这些反应的缓慢生物分子运动。 为了克服这些挑战，在未来五年中，我们的研究计划将扩大我们目前的努力 开发和采用多尺度模拟方法来了解（1）光调节信号活动 通过合成分子开关的瞬时受体电位通道和代谢型谷氨酸受体， 这是光遗传学和光药理学最受关注的，以及（2）长程电子转移事件 在隐花色素和电子分叉酶中，它们是理解生物钟的基础， 生物体中的磁场传感和能量代谢。我们方法的独特优势 包括 (1) 准确高效的非绝热动力学模拟，以及“即时”从头计算 核梯度和电子耦合； (2) 高质量非绝热动力学的有效集成 对蛋白质构象变化进行高效 MM 采样模拟。这些关键方法论 优势将使复杂的非绝热化学反应性的综合表征成为可能 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动力学并不常见，尤其是 所提出的多尺度模拟框架包含从头算非绝热动力学模拟。 因此，未来五年，我们的研究将为下一代的设计原则提供新的见解。 产生副作用最小的光化疗，创建强大的模拟计算工具 生物分子中的电子转移，加深我们对量子力学作用的基本理解 在一般生物学中。

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.