Understanding electronically non-adiabatic reactions in biomolecules with multiscale simulations

梁实验室使用分子模拟从根本上了解电子非

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.