Research

My research interests lie at the interface between theoretical/computational chemistry and biophysics. The research in our lab is directed toward understanding how biomolecules perform their functions via dynamical motions that are encoded in their three dimensional structures. The primary research tool we use is computer simulations.

Many essential functions of living cells are performed by nanoscale motors consisting of protein complexes. The ability of these biomolecular motors to utilize chemical free energy to perform mechanical work makes them splendid molecular machines. Among various types of molecular motors, ATP binding cassette (ABC) transporter represents a unique family of motor proteins that enable the translocations of various substrates, including small organic/inorganic molecules, across the cell membrane, by harnessing the free energy associated with ATP binding and hydrolysis. Dysfunctions of ABC-transporters have been linked to a number of diseases, including cystic fibrosis, the most common fatal hereditary disease in the US. The over expressions of certain ABC-transporters are also known to contribute to multidrug resistance of tumor cells after cancer patients receive chemotherapy. In bacterial cells, ABC- transporters are responsible for extrusions of various antibiotics. Given these important clinic implications, intensive experimental efforts have been put on structural biology to elucidate the structure/function relationship of ABC-transporters, highlighted by the recent success of obtaining several high-resolution x-ray crystal structures. However, the complexity of the system makes the direct measurements of the dynamics of the essential conformational changes very difficult, where molecular dynamics simulations provide a powerful tool to obtain a detailed understanding of these processes. One research project in our lab is aimed at obtaining a deeper understanding of conformational dynamics, enzyme catalysis, as well as the chemomechanical coupling mechanisms under which the chemical free energy is converted into mechanical work in ABC-transporters. The proposed multiscale simulations that integrate coarse-grained modeling, alchemical free energy computations, and combined quantum mechanical/molecular mechanical calculations will establish an essential link between the static structures, as determined by x-ray crystallography, and the dynamical aspects of the motor functions.

Another research direction we are interested in pursuing is to develop computational tools to study electron transfers (ETs) in biology. In order to provide a quantitative description of the contribution from the protein environment to a biological ET process, we plan to develop a new combined quantum mechanical/molecular mechanical (QM/MM) approach, in which the ET reactive system is described by quantum mechanics, and the surrounding solvent and protein fragments are treated by a molecular mechanical force field. We anticipate to apply the method to study the self-exchange reaction of an intramolecular electron transfer between two ion-sulfur clusters in Ferredoxin. The long-term goal is to elucidate the mechanism of the electron transfer step in DNA-photolyases, which recognize and repair damaged DNA with cyclobutane pyrimidine dimer lesions caused by UV-radiation.

Education

• B.S., Peking University, Beijing, 1999
• Ph.D., University of Minnesota, 2004
• Postdoctoral fellow, University of Minnesota, 2004-2005
• Postdoctoral fellow, Harvard University, 2005-2010

Publications & Professional Activity

Ojeda-May, P.; Pu, J. "Treating electrostatics with Wolf summation in combined quantum mechanical and molecular mechanical simulations," in J. Chem. Phys. 2015, 143, pp. 174111.

Karplus, M.; Pu, J. "How Biomolecular Motors Work: Synergy between Single Molecule Experiments and Single Molecule Simulations," in Springer Series in Chemical Physics 2010, 96 (Single Molecule Spectroscopy in Chemistry, Physics, and Biology), pp. 271-285.

Brooks, B. R.; Brooks, C. L., III; Mackerell, A. D., Jr.; Nilsson, L.; Petrella, R. J.; Roux, B.; Won, Y.; Archontis, G.; Bartels, C.; Boresch, S.; Caflisch, A.; Caves, L.; Cui, Q.; Dinner, A. R.; Feig, M.; Fischer, S.; Gao, J.; Hodoscek, M.; Im, W.; Kuczera, K.; Lazaridis, T.; Ma, J.; Ovchinnikov, V.; Paci, E.; Pastor, R. W.; Post, C. B.; Pu, J.; Schaefer, M.; Tidor, B.; Venable, R. M.; Woodcock, H. L.; Wu, X.; Yang, W.; York, D. M.; Karplus, M., "CHARMM: The biomolecular simulation program," J. Comput. Chem. 2009, 30, pp. 1545-1614.

Pu, J.; Karplus, M., "How Subunit Coupling Produces the γ-Subunit Rotary Motion in F1-ATPase," Proc. Natl. Acad. Sci. USA 2008, 105, pp. 1192-1197.

Xie, W.; Pu, J.; MacKerell, Jr. A. D.; Gao, J. "Development of a Polarizable Intermolecular Potential Function for Liquid Amides and Alkanes,” JCTC 2007, 3, pp. 1878-1889.

Pu, J.; Gao, J.; Truhlar, D. G., "Multidimensional Tunneling, Recrossing, and the Transmission Coefficient for Enzymatic Reactions," Chem. Rev. 2006, 106, pp. 3140-3169.

Pang, J.; Pu, J.; Gao, J.; Truhlar, D. G.; Allemann, R. K., "Hydride Transfer Reaction Catalyzed by Hyperthermophilic Dihydrofolate Reductase is Dominated by Quantum Mechanical Tunneling and is Promoted by Both Inter- and Intramonomeric Correlated Motions," J. Am. Chem. Soc. 2006, 128, pp. 8015-8023.

Pu, J.; Ma, S.; Garcia-Viloca, M.; Gao, J.; Truhlar, D. G.; Kohen, A., "Nonperfect Synchronization of Reaction Center Rehybridization in the Transition State of the Hydride Transfer Catalyzed by Dihydrofolate Reductase," J. Am. Chem. Soc. 2005, 127, 14879-14886.

Lin, H.; Zhao, Y.; Ellingson, B. A.; Pu, J.; Truhlar, D. G., "Temperature Dependence of Carbon-13 Kinetic Isotope Effects of Importance to Global Climate Change," J. Am. Chem. Soc. 2005, 127, 2830-2831.

Pu, J.; Ma, S.; Gao, J.; Truhlar, D. G., "Small Temperature Dependence of the Kinetic Isotope Effect for the Hydride Transfer Reaction Catalyzed by Escherichia coli Dihydrofolate Reductase," J. Phys. Chem. B 2005, 109, pp. 8551-8556.

Pu, J.; Gao, J.; Truhlar, D. G., "Combining Self-Consistent-Charge Density-Functional Tight-Binding (SCC-DFTB) with Molecular Mechanics by the Generalized Hybrid Orbital (GHO) Method," J. Phys. Chem. A 2004, 108, pp. 5454-5463.

Pu, J.; Gao, J.; Truhlar, D. G., "Generalized Hybrid Orbital (GHO) Method for Combining Ab Initio Hartree-Fock Wave Functions with Molecular Mechancis," J. Phys. Chem. A, 2004, 108, pp. 632-650.

Dutton, G.; Pu, J.; Truhlar, D. G.; Zhu, X. -Y., "Lateral Confinement of Image Electron Wavefunction by an Interfacial Dipole Lattice," J. Chem. Phys. 2003, 118, pp. 4337.

Pu, J.; Truhlar, D. G., "Tests of Potential Energy Surfaces for H + CH4 ® CH3+ H2: Deuterium and Muonium Kinetic Isotope Effects for the Forward and Reverse Reaction," J. Chem. Phys. 2002, 117, pp. 10675.

Pu, J.; Truhlar, D. G., "Parametrized Direct Dynamics Study of Rate Constants of H with CH4 from 250 to 2400 K," J. Chem. Phys. 2002, 116, pp. 1468.