Alexei Stuchebrukhov

Our group is working in the general area of computational chemistry and biological electron and proton transfer; our main current efforts are focused on understanding molecular aspects of the electron transport chain (ETC) of aerobic cells and biological energy transduction. We are particularly interested in molecular mechanisms of redox-driven proton pumps of ETC. In the past decade, we have been an integral part of the bioenergetics community, in particular active in cytochrome c oxidase (complex IV of ETC) studies. Our main contribution is a model of cytochrome c oxidase proton pump mechanism, which is recognized in the field. Part of our interests is related to proton transport along biological membranes, a subject closely related to operation of the ETC chain; we have made substantial contributions in this area, developed a theory of coupled surface and bulk diffusion, and explained the mechanism of proton migration along biological membranes. Our most original technical innovation concerns the description of electron tunneling in proteins. Our method of tunneling currents is the basis of modern first principles simulations of biological electron transfer. The problems of electron and proton transfer naturally involve molecular dynamics, quantum chemistry, electrostatics, pKa calculations, and modeling. Along with applications, we also conduct research in methods development, as the need arises. Our work on charge-scaling models in molecular simulations is well recognized in theoretical community. Major part of current work involves application of computational methods developed by our group to study electron transport in NADH dehydrogenase (complex I of ETC) and its redox-driven proton pumping mechanism in collaboration with structural biology experimental experts who solved the enzyme structure. 

Our studies include all enzymes of the respiratory chain. Our long-term goal to map the whole electron transport chain in mitochondria, to identify molecular mechanisms of redox-driven proton pumping, oxygen reduction, and generation of Reactive Oxygen Species (ROS).  The importance of such studies is underscored by the growing evidence that the dysfunction of the electron transport chain in mitochondria and free radical production are contributing to cell aging, apoptosis, and to a number of degenerative diseases of the heart and brain in humans.

Education, Awards and Professional Highlights

• BPH Advising and Mentoring Award, UC Davis (2022)
• Outstanding Mentor Faculty Award, University Honors Program, UC Davis (2017)
• Arnold and Mabel Beckman Foundation Young Investigator (1997)
• Alfred P. Sloan Foundation Fellow (1996)
• Appointed to faculty, UC Davis (1994)
• Invited Lecturer, Princeton University (1991)
• Research Associate, California Institute of Technology (1990-1994)
• Ph.D. Theoretical Chemical Physics, Moscow Physical and Technical Institute, P.N. Lebedev Physical Institute, Acad. Sci. USSR (1985)

Representative Publications

1. We have developed ab initio quantum chemistry theory of calculations of rates and pathways of electron tunneling in proteins. Our method of Tunneling Currents is the basis of state-of-the-art fist-principles calculations of electron transfer reactions in proteins. 

• Stuchebrukhov, A. A., Toward Ab Initio Theory of Long-Distance Electron Tunneling in Proteins: Tunneling   Currents Approach. Adv. Chem. Phys. 2001, 118, 1-44.
• Stuchebrukhov, A. A., Long-Distance Electron Tunneling in Proteins. Theor. Chem. Acc. 2003, 110, 291-306.
• Stuchebrukhov, A.A., Tunneling Time and the Breakdown of Born-Oppenheimer Approximation in Long-Distance Electron Transfer Reactions. J. Phys. Chem. B 2016, 120, 1408-1417.

2. We have developed theory of Proton Coupled Electron Transfer Reactions (PCET). This theory is the basis of treatment of both adiabatic and non-adiabatic PCET reactions in proteins.

• Hammes-Schiffer, S.; Stuchebrukhov, A. A., Theory of Coupled Electron and Proton Transfer Reactions. Chem. Rev. 2010, 110, 6939-6960.

3. We have developed theory of proton migration along biological membranes, which is a part of local chemiosmotic theory of bioenergetics.

• Medvedev, E. S.; Stuchebrukhov, A. A., Proton Diffusion Along Biological Membranes. J. Phys. Condensed Matter 2011, 23.
• Medvedev, E. S.; Stuchebrukhov, A. A., Mechanism of Long-Range Proton Translocation Along Biological Membranes. FEBS Lett. 2013, 587, 345-349.

4. We have developed a model, and pioneered calculations, of redox-driven proton pumping mechanism in cytochrome c oxidase (complex IV of the respiratory chain), which is well recognized in the field. The central concept of Proton Loading Site (PLS), an integral part of all redox-driven proton-pumping theories was developed in our studies.

• Popovic, D. M.; Stuchebrukhov, A. A., Proton Pumping Mechanism and Catalytic Cycle of Cytochrome C Oxidase: Coulomb Pump Model with Kinetic Gating. FEBS Lett. 2004, 566, 126-130.
• Quenneville, J.; Popovic, D. M.; Stuchebrukhov, A. A., Combined DFT and Elecrostatic Study of the Proton Pumping Mechanism of Cytocrome C Oxidase. Biochim. Biophys. Acta 2006, 1035-1046.
• Stuchebrukhov, A. A., Redox-Driven Proton Pumps of the Respiratory Chain. Biophys. J. 2018, 115, 830-840.

5. We have pioneered electron tunneling calculations in NADH dehydrogenase, complex I of the respiratory chain.

• Hayashi, T.; Stuchebrukhov, A. A., Electron Tunneling in Respiratory Complex I. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 19157-19162.

Additional representative publications:

• Stuchebrukhov, A. A., Redox-Driven Proton Pumps of the Respiratory Chain. Biophys. J. 2018, 115, 830-840.
• Ni, Y.; Hagras, M. A.; Konstantopoulou, V.; Mayr, J. A.; Stuchebrukhov, A. A.; Meierhofer, D., Mutations in Complex I NDUFS1 Cause Metabolic Reprogramming and Disruption of the Electron Transport Chain. Cells 2019, 8, 1149.
• Hayashi, T.; Stuchebrukhov, A. A., Electron Tunneling in Respiratory Complex I. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 19157-19162.
• Hagras, M. A.; Stuchebrukhov, A. A., Concerted Two-Electron Reduction of Ubiquinone in Respiratory Complex I. J. Phys. Chem. B 2019, 123 (25), 5265-5273.
• Hammes-Schiffer, S.; Stuchebrukhov, A. A., Theory of Coupled Electron and Proton Transfer Reactions. Chem. Rev. 2010, 110, 6939-6960.

And more:

•  Stuchebrukhov, A.A., Watching DNA Repair in Real Time. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 19445-19446.
• Hagras, M.; Stuchebrukhov, A., Inhibition of respiratory complex III by ligands that interact with a regulatory switch inducing ROS production US Patent No: 11,058,654 B2 issued Jul 13, 2021.
• Hagras, M. A.; Stuchebrukhov, A. A., Electron tunneling in proteins program. J. Comput. Chem. 2016, 37 (15), 1388-1395.
• Morozenko, A.; Stuchebrukhov, A. A., Dowser++, a new method of hydrating protein structures. Proteins: Struct., Funct., Bioinf. 2016, 84 (10), 1347-1357.
• Farahvash, A.; Stuchebrukhov, A., The Many Roles of Internal Water in Cytochrome c Oxidase. J. Phys. Chem. B 2018, 122 (31), 7625-7635.
• Hagras, M. A.; Stuchebrukhov, A. A., Transition Flux Formula for the Electronic Coupling Matrix Element. J. Phys. Chem. B 2015, 119 (24), 7712-7721.
• Farahvash, A.; Leontyev, I.; Stuchebrukhov, A., Dynamic and Electronic Polarization Corrections to the Dielectric Constant of Water. J. Phys. Chem. A 2018, 122 (48), 9243-9250.
• Leontyev, I. V.; Stuchebrukhov, A. A., Polarizable molecular interactions in condensed phase        and their equivalent nonpolarizable models. J. Chem. Phys. 2014, 141 (1).
• Stuchebrukhov, A. A. Mechanisms of proton transfer in proteins. Localized charge transfer versus delocalized soliton transfer. Phys. Rev. E 79, 031927 (2009).
• Couch, V.; Stuchebrukhov, A., Proteins as strongly correlated protonic systems. FEBS Lett. 2012, 586 (5), 519-525.