Bertrand García-Moreno is Professor and Chair of the Jenkins Department of Biophysics. His research is focused on experimental and computational protein science, including: electrostatics, structure-based energy calculations, pH effects, engineering of pH switches and evolution and stability in extreme environments.
Research in our lab examines the structural and physical basis of solution properties of proteins such as stability, dynamics, and the sensitivity to physical properties of their environment (pressure, temperature, pH, salt). We have active projects in these areas:
PROTEIN ELECTROSTATICS:Many essential biological processes (e.g. catalysis, redox reactions, H+transfer, recognition and binding) are governed by electrostatics forces in proteins. To understand the structural basis of these processes it is necessary to understand how the structures of proteins determine their electrostatic properties. To this end, accurate algorithms for structure-based energy calculations are needed. To guide the development of computational algorithms we study the fundamental physical character of electrostatic effects in proteins with experimental approaches (crystallography, NMR spectroscopy and equilibrium thermodynamics).
ENERGY TRANSDUCING:The property common to all living cells is their ability to convert one form of energy (e.g. light) into another (e.g. chemical bonds). Proteins are the molecules in charge of biological energy transduction. We study the most important structural motif used for energy transduction, consisting of H+binding groups buried in hydrophobic environments in proteins. The properties of these buried groups are poorly understood, highly anomalous, and they cannot be reproduced with computational models. We are especially interested in experimental characterization of the dielectric response of proteins (i.e. their dynamic response to ionization events) that enables energy transduction.
PROTEIN ENGINEERING:pH is tightly regulated in physiological environments. Not surprisingly, abnormal cellular pH is associated with many pathological condition, notably cancer and Alzheimer’s disease. With the goal of improving protein therapeutics against cancer we apply fundamental principles of statistical thermodynamics and of classical electrostatics to engineer protein pH switches that respond with a large conformational change to very small changes in pH in the physiological pH range.
EXTREME BIOPHYSICS:Most life on earth exists under extreme conditions of one or more physical variables (pressure, temperature, pH and salt concentration). If life exists elsewhere in the universe, it is likely to exist under extreme conditions as well. We study the molecular mechanisms used by proteins to tolerate extreme environments as well as how proteins evolved in response to changing physical conditions on Earth 4 during billion years of evolution.
- A. C. Robinson, J. L. Schlessman, and B. Garcia-Moreno E. (2018) Dielectric properties of a protein probed by reversal of a buried ion pair J. Phys. Chem. B. 122: 2516-2524
- C. M. Kougentakis, E. M. Grasso, A. Majumdar and B. Garcia-Moreno E. (2018) Anomalous properties of Lys residues buried in the hydrophobic interior of a protein revealed with 15N-detect NMR spectroscopy J. Phys. Chem. Letters9: 383-387
- M. T. Peck, G. Ortega-Quintanilla, J. N. De Luca-Johnson, J. L. Schlessman, A. R. Robinson and B. Garcia-Moreno E. (2017) Local backbone flexibility as a determinant of the apparent pKa values of buried ionizable groups in proteins Biochemistry 56:5338-5346
- A. C. Robinson, A. Majumdar, J. L. Schlessman and B. Garcia-Moreno E. (2016) Charges in hydrophobic environments: a strategy for identifying alternative states in proteins Biochemistry 56: 212-218.
- D. E. Richman, A. Majumdar, and B. Garcia-Moreno E. (2015) Conformational reorganization coupled to the ionization of Lys residues in proteins Biochemistry 54: 5888-5897.
- C. A. Fitch, G. Platzer, M. Okon, B. Garcia-Moreno E., and L. P. McIntosh (2015) Arginine: its pKa value revisited Protein Science 24: 752-761.
- D. E. Richman, A. Majumdar, and B. García-Moreno E. (2014) pH dependence of conformational fluctuations of the protein backbone Proteins: Struct. Funct. Bioinf. 82: 3132-3143.
- A. C. Robinson, C. A. Castañeda, J. L. Schlessman and B. García-Moreno E. (2014) Structural and thermodynamic consequences of burial of an artificial ion pair in the hydrophobic interior of a protein Proc. Natl. Acad. Sci. USA 111: 11685-11690.
- J. Roche, M. Dellarole, J. A. Caro, D. R. Norberto, A. E. García, B. Garcia-Moreno E., C. Roumestand and C. A. Royer (2013) Effect of internal cavities on folding rates and routes revealed by real-time pressure jump NMR spectroscopy J. Am. Chem. Soc. 135:14610-14618.
- M. Dellarole, K. Kobayashi, J-B. Rouget, J. Caro, J. Roche, M. Islam, B. García-Moreno E., Y. Kuroda and C. A. Royer. (2013) Probing the physical determinants of thermal expansion of folded proteins J. Phys. Chem. B117: 12742-12749.
- J. Roche, J. A. Caro, J. A., Norberto, D. R., Barthe, P., Roumestand, C., Schlessman, J. L., Garcia, A. E., B. García-Moreno E., & C. A. Royer (2012) Cavities determine the pressure unfolding of proteins Proc. Natl. Acad. Sci. USA109: 6945-6950.
- M. S. Chimenti, V. S., Khangulov, A. C. Robinson, A. Heroux, A. Majumdar, J. L. Schlessman, & García-Moreno E. B. (2012) Structural reorganization triggered by charging of Lys residues in the hydrophobic interior of a protein. Structure20: 1-15.
- J. E. Nielsen, M. R. Gunner, & B. García-Moreno E. (2011) The pKa Cooperative: A collaborative effort to advance structure-based calculations of pKa values and electrostatic effects in proteins. Proteins: Struct. Funct. Bioinf. 79: 3249-3259.
- D. G. Isom, C. A. Castañeda, B. R. Cannon & B. García-Moreno E. (2011) Large Shifts in pKa Values of Lysine Residues Buried Inside a Protein. Proc. Natl. Acad. Sci. USA108: 5260-5265.
- M. J. Harms, J. L. Schlessman, G. R. Sue, & B. García-Moreno E. (2011) Arginine residues at internal positions in a protein are always charged Proc. Natl. Acad. Sci. USA 18954-18959