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Multiscale simulation of photoactive biomolecules


Our group's research efforts are focused on developing and applying new multiscale simulation methods to study the photoactive biomolecules that are essential in photopharmacology, biomedical imaging and photocatalysis, with the eventual goal of providing design principles to enhance their efficiency. The unique aspect of our multiscale simulation approach is that we bridge the accurate quantum mechanical treatment of photochemical reactions and the efficient molecular mechanics modeling of biomolecular motion.

Photoactive biological systems have promising applications in biomedical and energy sciences. Understanding photochemical reactions in biomolecules with molecular-level detail is critical for improving the design of new photoactive proteins, and molecular simulation is now ready to achieve this goal with ever-increasing capability. However, the multiscale nature of the photocontrolled biological systems poses significant challenges for simulation. Specifically, the photochemical reactions occur on short timescale and lengthscale, and typical force-field based simulations cannot describe their quantum mechanical nature. Meanwhile, the biomolecular motions initiated by the photochemical reactions occur on long timescale and lengthscale, and are beyond the reach of most quantum mechanical simulations. To address these challenges, we combine ab initio non-adiabatic dynamics simulation, force-field based molecular mechanics modeling, first principle electronic structure calculation, and enhanced sampling techniques to understand the multiscale nature of photoactive biomolecules.

Research projects in our group include:

  • Light control of protein activity by molecular photoswitches in photopharmacology

Using light to control protein activity is crucial for next-generation biomedical science because of its high spatiotemporal precision. One popular approach to achieve light control is to link proteins with molecular photoswitches such as azobenzene-derived compounds. Despite the success of this approach in recent years, several important questions remain to be answered in order to improve the photocontrol efficiency by molecular photoswitches. For example, how can we achieve high photoisomerization quantum yield and long absorption wavelength in protein environment? How can we maximize the difference in the protein’s function as a result of the photoisomerization reaction?

In order to investigate these questions, we combine ab initio non-adiabatic dynamics simulation and molecular mechanics modeling to understand the molecular mechanism underlying the photocontrol of proteins by molecular photoswitches. Such insights will eventually lead to better design principles for molecular photoswitches to be used as light-activatable drugs in precision medicine.

  • Aggregation-induced emission phenomenon in biomedical imaging

Fluorescence imaging is an important tool for disease diagnosis. In the past two decades, many organic fluorescent molecules were designed to possess aggregation-induced-emission (AIE) characteristics. The AIE-based fluorophore has enhanced fluorescence in the aggregate state compared to in solution, because the intramolecular motion leading to non-radiative decay is restricted when the fluorophore is in the aggregate. Compared to the traditional fluorophores, AIE-based fluorophores can detect biomolecules with high sensitivity and selectivity. Despite these advantages, there remain many challenges to improve their performance. Specifically, development of AIE-based fluorophores with increased fluorescence quantum yield, fluorescence wavelength and target selectivity are still necessary for next-generation bio-imaging technologies.


To achieve this goal, we develop multiscale simulation framework to study the fluorescence mechanism of the AIE-based fluorophores in biomolecules. Combining docking simulations, molecular dynamics simulations and free energy calculations, we aim to predict the fluorophore's selectivity of the target biomolecules. Using the ab initio excited-state molecular dynamics simulation with the quantum mechanics/molecular mechanics (QM/MM) scheme, we aim to quantify the fluorescence wavelength, the excited state lifetime and fluorescence quantum yield. Such information will be valuable for the design of highly sensitive and selective AIE-based fluorophores.

  • Water splitting reaction catalyzed by photosystem II for renewable energy generation


Photosystem II (PSII) is essential for photosynthesis. It catalyzes the water photodissociation reaction and initiates the light-dependent reactions of photosynthesis. Understanding the mechanism of the proton-coupled electron transfer (PCET) reactions catalyzed by the oxygen-evolving complex (OEC) in PSII is necessary for the design of artificial water-splitting catalysts. Previous experimental and computational studies on PSII mainly focused on the static structures and the energetics of the intermediates of OEC. However, many important questions remain to be answered regarding the dynamical aspects of the PCET reactions connecting these intermediates, e.g., how are the proton and electron transfer events dynamically coupled to each other? How is the PCET mechanism influenced by the protein environment? Ab initio non-adiabatic dynamics simulations are necessary to answer such questions. However, one major challenge for such simulations is to accurately and efficiently describe the electronic structure of the OEC.

To overcome this challenge, we combine ab initio non-adiabatic dynamics method and GPU-accelerated advanced electronic structure methods to study the non-adiabatic dynamics of the PCET reactions in PSII. The simulations will provide new insight into the design principles of artificial water-splitting catalysts. 

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