Dr. Ruibin Liang

Principal Research Interests

• Multiscale Simulation of Photoactive Biomolecules
• Quantum Dynamics and Classical Dynamics Simulation
• Electronic Structure Calculation
• Enhanced Sampling Simulation

Our group's major efforts are focused on developing and applying new multiscale simulation methods to study the photoactive biomolecules that are essential in photopharmacology and bioenergetics, 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.

 

• 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.​

• Photoinduced electron transfer and electron bifurcation in proteins

Electron transfer (ET) is fundamental for signal conduction and energy conversion in living organisms. Ultrafast photoinduced ET occurs in cryptochromes, which is a key component of the circadian clock and associated with diseases such as seasonal affective disorder, bipolar disorder, and depression. As another example, electron bifurcation separates two electrons from one donor to one branch of high-reduction-potential cofactors and the second branch of low-potentials cofactors, generating strong reductants for downstream processes. A well-known electron bifurcating enzyme is Complex III in the electron transport chain, where it extracts two electrons from the fully-reduced ubiquinol and delivers one to cytochrome c­1 and the other to cytochrome b in the Q-cycle. Electron bifurcation has been recognized as a general and fundamental mechanism of energy conservation in life.

​Despite decades of study, many fundamental questions about ET in these biomolecules remain elusive. For example, how does nature prevent electron backflow and short-circuits to ensure high-efficiency charge separation? How do the electrostatics and dynamics of the protein affect the ET rate and electronic coherence between cofactors? Simulations quantifying the thermodynamics and dynamics of ET are necessary for answering these questions. However, such simulations are challenging due to the multiscale nature of biological ET: changes in the electronic state often couple with large and slow structural changes of biomolecules. Well-established ET models such as Marcus theory are undoubtedly very successful at describing biological ET, but they also have limitations. For example, the assumption of equilibrium statistical mechanics is often questionable in the regime of ultrafast ET in biomolecules such as cryptochromes, where nonergodic effects are prominent. Moreover, these models lack atomic-level details of real-time ET dynamics in biomolecules. In this regard, ab initio non-adiabatic dynamics simulations are indispensable to complement traditional ET models, because they directly propagate the coupled motions of nuclei and electrons without introducing assumptions such as ergodicity and (non)adiabaticity. However, existing methods in this category are not capable of accurately and efficiently describing the electronic structure and quantum dynamics of biological ET. To overcome these challenges, we develop new ab initio non-adiabatic dynamics methods to provide an unbiased description of the ET dynamics at the all-atom and all-electron resolution. Our project generates a powerful tool for understanding biological electron transfer in general. These key methodological advantages enable us to comprehensively characterize the non-adiabatic reactivity in complex biomolecular systems with unprecedented accuracy. Furthermore, we integrate it with existing simulation tools and ET models in a multiscale simulation framework to understand ET in cryptochromes and electron-bifurcating enzymes.

Representative Publications

* equal contribution

• Costa GJ, Liang R*. Decrypting the Nonadiabatic Photoinduced Electron Transfer Mechanism in Light-Sensing Cryptochrome. ACS Central Science. 2025 May. doi: 10.1021/acscentsci.5c00376.
• Pandey A, Costa GJ, Alam M, Poirier B*, Liang R*. Development of Parallel On-the-Fly Crystal Algorithm for Reaction Discovery in Large and Complex Molecular Systems. J Chem Theory Comput. 2025 May 13; 21(9):4704-4717. doi: 10.1021/acs.jctc.5c00324. Epub 2025 May 1. PubMed PMID: 40310761; PubMed Central PMCID: PMC12080108.
• Pandey A, Poirier B*, Liang R*. Development of Parallel On-the-Fly Crystal Algorithm for Global Exploration of Conical Intersection Seam Space. J Chem Theory Comput. 2024 Jun 11; 20(11):4778-4789. doi: 10.1021/acs.jctc.4c00292. Epub 2024 May 22. PubMed PMID: 38775818.
• Costa GJ, Egbemhenghe A, Liang R*. Computational Characterization of the Reactivity of Compound I in Unspecific Peroxygenases. J Phys Chem B. 2023 Dec 28; 127(51):10987-10999. doi: 10.1021/acs.jpcb.3c06311. Epub 2023 Dec 14. PubMed PMID: 38096487.
• Costa GJ, Liang R*. Understanding the Multifaceted Mechanism of Compound I Formation in Unspecific Peroxygenases through Multiscale Simulations. J Phys Chem B. 2023 Oct 19; 127(41):8809-8824. doi: 10.1021/acs.jpcb.3c04589. Epub 2023 Oct 5. PubMed PMID: 37796883.
• Bakhtiiari A, Costa GJ, Liang R*. On the Simulation of Thermal Isomerization of Molecular Photoswitches in Biological Systems. J Chem Theory Comput. 2023 Sep 26; 19(18):6484-6499. doi: 10.1021/acs.jctc.3c00451. Epub 2023 Aug 22. PubMed PMID: 37607344.
• Liang R*, Bakhtiiari A. Multiscale simulation unravels the light-regulated reversible inhibition of dihydrofolate reductase by phototrexate. J Chem Phys. 2022 Jun 28; 156(24):245102. doi: 10.1063/5.0096349. PubMed PMID: 35778097.
• Liang R*, Bakhtiiari A. Effects of Enzyme-Ligand Interactions on the Photoisomerization of a Light-Regulated Chemotherapeutic Drug. J Phys Chem B. 2022 Mar 31; 126(12):2382-2393. doi: 10.1021/acs.jpcb.1c10819. Epub 2022 Mar 17. PubMed PMID: 35297246.
• Liang R*. First-Principles Nonadiabatic Dynamics Simulation of Azobenzene Photodynamics in Solutions. J Chem Theory Comput. 2021 May 11; 17(5):3019-3030. doi: 10.1021/acs.jctc.1c00105. Epub 2021 Apr 21. PubMed PMID: 33882676.
• Liang R, Yu JK, Meisner J, Liu F, Martinez TJ*. Electrostatic Control of Photoisomerization in Channelrhodopsin 2. J Am Chem Soc. 2021 Apr 14; 143(14):5425-5437. doi: 10.1021/jacs.1c00058. Epub 2021 Apr 1. PubMed PMID: 33794085.
• Liang R, Liu F, Martínez TJ*. Nonadiabatic Photodynamics of Retinal Protonated Schiff Base in Channelrhodopsin 2. J Phys Chem Lett. 2019 Jun 6; 10(11):2862-2868. doi: 10.1021/acs.jpclett.9b00701. Epub 2019 May 16. PubMed PMID: 31083920.
• Liang R, Cotton SJ, Binder R, Hegger R, Burghardt I*, Miller WH*. The symmetrical quasi-classical approach to electronically nonadiabatic dynamics applied to ultrafast exciton migration processes in semiconducting polymers. J Chem Phys. 2018 Jul 28; 149(4):044101. doi: 10.1063/1.5037815. PubMed PMID: 30068189.
• Liang R, Swanson JMJ, Madsen JJ, Hong M, DeGrado WF*, Voth GA*. Acid activation mechanism of the influenza A M2 proton channel. Proc Natl Acad Sci U S A. 2016 Nov 8; 113(45):E6955-E6964. doi: 10.1073/pnas.1615471113. Epub 2016 Oct 24. PubMed PMID: 27791184; PubMed Central PMCID: PMC5111692.
• Liang R, Swanson JMJ*, Wikström M, Voth GA*. Understanding the essential proton-pumping kinetic gates and decoupling mutations in cytochrome c oxidase. Proc Natl Acad Sci U S A. 2017 Jun 6; 114(23):5924-5929. doi: 10.1073/pnas.1703654114. Epub 2017 May 23. PubMed PMID: 28536198; PubMed Central PMCID: PMC5468613.
• Liang R, Swanson JM, Peng Y, Wikström M, Voth GA*. Multiscale simulations reveal key features of the proton-pumping mechanism in cytochrome c oxidase. Proc Natl Acad Sci U S A. 2016 Jul 5; 113(27):7420-5. doi: 10.1073/pnas.1601982113. Epub 2016 Jun 23. PubMed PMID: 27339133; PubMed Central PMCID: PMC4941487.
• Liang R, Li H, Swanson JM, Voth GA*. Multiscale simulation reveals a multifaceted mechanism of proton permeation through the influenza A M2 proton channel. Proc Natl Acad Sci U S A. 2014 Jul 1; 111(26):9396-401. doi: 10.1073/pnas.1401997111. Epub 2014 Jun 16. PubMed PMID: 24979779; PubMed Central PMCID: PMC4084430.
• Lee S*, Liang R*, Voth GA, Swanson JM*. Computationally Efficient Multiscale Reactive Molecular Dynamics to Describe Amino Acid Deprotonation in Proteins. J Chem Theory Comput. 2016 Feb 9; 12(2):879-91. doi: 10.1021/acs.jctc.5b01109. Epub 2016 Jan 20. PubMed PMID: 26734942; PubMed Central PMCID: PMC4750100.