Bertrand García-Moreno

Professor and Chair

002 Jenkins Hall
410-516-4497
bertrand@jhu.edu
Group/Lab Website

Biography
Research
Publications

Bertrand García-Moreno is a professor and the department chair of the Department of Biophysics. His research focuses on experimental and computational studies of protein electrostatics, structure-based energy calculations, and ligand-driven conformational transitions.

Structure, Energy, and Function of Proteins and Macromolecular Assemblies

Understanding the relationship between the structure, function and energetics of proteins is one of the central problems in biochemistry today. Electrostatics govern many key biochemical processes, therefore one of our top priorities is to develop an understanding of electrostatic effects in proteins. Students in our laboratory are working on the following projects:

  1. Many of the biological processes that are governed by electrostatics, such as catalysis, redox reactions, proton and electron transport, photoactivation, ion selectivity, and ligand recognition and binding, take place in environments secluded from solvent, such as in the protein interior of at interfaces between molecules. Calculations of electrostatic effects with existing computational methods fail dramatically in the case of buried ionizable groups. To further understand the character of electrostatic effects in these environments we are studying the energetics of ionization of buried groups experimentally. Our goal is to understand the physical and structural reasons why the protein interior behaves like a medium of high polarizability, in contrast with what is predicted from first principles or by extrapolation from the behavior of similar materials. We have discovered that water penetrates easily into the hydrophobic core or proteins and we are exploring physico-chemical properties of proteins that are affected by solvent penetration.
  2. We are also studying the contributions by electrostatics to stability and recognition in proteins. At present we are focused on studies of electrostatic effects in the denatured states of proteins because we have demonstrated experimentally that, at least in the denatured state of staphylococcal nuclease, there are very strong electrostatic interactions. We have learned how to use proton binding measurements to estimate the stability of the denatured states of nuclease––indirectly, we are also learning about the determinants of structure and compactness in the denatured state.
  3. We are studying the molecular mechanism of acid denaturation of staphylococcal nuclease. Our goal is to improve our understanding of the balance of forces in proteins and of the mechanisms whereby changes in solution conditions can trigger conformational transitions in proteins.
  4. Viruses are macromolecular assemblies that can sense and respond to changes in the ionic properties of their environment. Changes in pH and salts can trigger conformational transitions relevant to their cycle of infection. We study the molecular mechanisms whereby changes in salt and pH can trigger the conformational transitions in icosahedral viral capsids that are required for presentation of the viral genome to the replication machinery of the host cell. We are mapping the effects of solution conditions on stability with a variety of physical and biochemical techniques, and employ the crystallographic structures of viruses to interpret the measured energetics structurally.

Algorithms for structure-based energy calculations represent a powerful approach for connecting high resolution structures and the energetics measured experimentally. We are involved in the design, implementation and testing of semi-empirical algorithms for structure-based calculation of electrostatic energies in proteins. The algorithms for structure-based energy calculations are based on classical electrostatics and on the principles of statistical thermodynamics. One of the specific problems that we are studying concerns the treatment of site-bound waters in pKa calculations.

  • Pais, T.M., P. Lamosa, B. García-Moreno E., D.L. Turner, and H. Santos. (2009) Relationship between protein stabilization and protein rigidification induced by Mannosylglycerate. J. Mol. Biol. (in press).
  • Damjanovic, A., B. García-Moreno E., and B.R. Brooks. (2009) Self-guided Langevin dynamics study of regulatory interactions in NtrC. Proteins: Struc. Func. Bioinf. 76:1007-1019.
  • Castañeda, C.A., C.A. Fitch, A. Majumdar, V. Khangulob, J.L. Schlessman, and B. García-Moreno E. (2009) Molecular determinants of the pKa values of Asp and Glu residues in staphylococcal nuclease. Proteins: Struc. Func. Bioinf. 77:570-588.
  • Harms, M.J., C.A. Castañeda, J.L. Schlessman, G.R. Sue, D.G. isom, B.R. Cannon, and B. García-Moreno E. (2009) The pKa values of acidic and basic residues buried at the same internal location in a protein are governed by different factors. J. Mol. Biol. 389:34-47.
  • Takayama, Y., C.A. Castañeda, M.A. Chimenti, B. García-Moreno E., and J. Iwahara (2008) Direct evidence for deprotonation of a lysine side chain buried in the hydrophobic core of a protein. J. Am. Chem. Soc. 130:6714-6715.
  • Schlessman, J.L., C. Abe, A. Gittis, D.A. Karp, M.A. Dolan, and B. García-Moreno E. (2008) Crystallographic study of hydration of an internal cavity in engineered proteins with buried polar or ionizable groups. Biophys. J. 9:3208-316.
  • Fitzkee, N.C., and B. Garcia-Moreno E. (2008) Electrostatic effects in unfolded staphylococcal nuclease. Protein Sci. 17: 216-227.
  • Isom, D.G., B.R. Cannon, C.A. Castanñeda, A. Robinson, and B. García-Moreno E. (2008) High tolerance for ionizable residues in the hydrophobic interior of proteins. Proc. Natl. Acad. Sci. USA 105:17784-17788.
  • Harms, M.J., J.L. Schlessman, M.S. Chimenti, G.R. Sue, A. Damjanovic, and B. García-Moreno E. (2008) A buried lysine that titrates with a normal pKa: role of conformational flexibility at the protein water interface as a determinant of pKa values. Protein Sci. 17:833-845.
  • Damjanovic, A., X. Wu, B. García-Moreno E., and B.R. Brooks (2008) Backbone relaxation coupled to the ionization of internal groups in proteins: A self-guided Langevin Dynamics Study. Biophy. J. 95:4091-4101.
  • Baran, K.L., M.S. Chimenti, J.L. Schlessman, C.A. Fitch, K.J. Herbst, and B. García-Moreno E. (2008) Electrostatic effects in a network of polar and ionizable groups in staphylococcal nuclease. J. Mol. Biol. 379:1045-1062.