Bertrand García-Moreno

Bertrand García-Moreno

Professor; Executive Vice Dean

Contact Information

Research Interests: Experimental and computational studies of protein electrostatics, structure-based energy calculations, ligand-driven conformational transitions

Education: PhD, Indiana University

Bertrand García-Moreno is a Professor in the Jenkins Department of Biophysics and the Krieger School of Arts and Sciences Executive Vice Dean. 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.

AS.250.253 - Protein Engineering and Biochemistry Lab

AS.250.314 & 317 - Research in Protein Design and Evolution

AS.250.401 - Advanced Seminar in Structural and Physical Virology

AS.250.403 - Bioenergetics: Origins, Evolution and Logic of Living Systems

AS.250.689 - Physical Chemistry of Biological Macromolecules


  • 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


002 Jenkins Hall
3400 N. Charles Street
Baltimore, MD 21218

(410) 516-4497 office
(410) 516-4498 lab
(410) 516-4118 fax

Active Projects in our Lab

  • 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 or at interfaces between molecules. Calculations of electrostatic effects with existing computational methods fail dramatically in these environments. To address these problems we are studying the energetics of ionization of buried groups. The approach entails experiments to identify the processes that contribute to the polarizability in the protein interior and to obtain the data needed to improve and to test computational methods for structure-based energy calculations.
  • We are studying the molecular determinants of pKa values of surface ionizable residues. This entails mapping contributions from short-range and long-range coulombic interactions, hydrogen bonding, packing, degree of exposure to solvent, etc. More recently we have begun to explore the hypothesis that local conformational fluctuations are important determinants of pKa values. In a related project we are studying the molecular mechanism of acid denaturation of staphylococcal nuclease. Our goal is to improve understanding of the balance of forces in proteins and of the mechanisms whereby changes in solution conditions trigger conformational transitions in proteins.
  • Viruses are macromolecular assemblies that can sense and respond to minute changes in the ionic properties of their environment. Changes in pH and ion concentration can trigger conformational transitions essential for the viral life cycle. We study the molecular mechanisms in icosahedral viral capsids whereby changes in environmental signals can trigger conformational transitions required for presentation of the viral genome to the replication machinery of the host cell. This involves mapping the effects of solution conditions on virus stability with a variety of physical and biochemical techniques. Crystallographic structures of viruses are used to interpret the measured energetics structurally.
  • Algorithms for structure-based energy calculations represent a powerful approach for connecting high resolution structures and functional energetics. 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 and the coupling between changes in pKa values and conformational transitions.

BGME Lab People

Former Members

  • Dr. Ana Damjanovic
  • Dr. Carolyn Fitch
  • Dr. Kelli Barran
  • Dr. Brian Cannon
  • Dr. Alfredo Caro
  • Dr. Carlos Castañeda
  • Dr. Michael Chimenti
  • Dr. Brian Doctrow
  • Dr. Michael Harms
  • Dr. Daniel Isom
  • Dr. Daniel Karp
  • Dr. Victor Khangulov
  • Dr. Jaime Sorenson
  • Peregrine Bell-Upp

Former Undergrads

  • Janine Lin
  • Nijay Patel
  • Meredith Peck
  • Lauren Skerritt
  • Gloria Sue

Selected Publications:

Harms MJ, Schlessman JL, Sue GR, García-Moreno B. Arginine residues at internal positions in a protein are always charged. Proc Natl Acad Sci U S A. 2011 Nov 22; 108 (47) :18954-9.

Damjanovic A, Brooks BR, García-Moreno B. Conformational relaxation and water penetration coupled to ionization of internal groups in proteins. J Phys Chem A. 2011 Apr 28; 115 (16) :4042-53.

Isom DG, Castañeda CA, Cannon BR, García-Moreno B. Large shifts in pKa values of lysine residues buried inside a protein. Proc Natl Acad Sci U S A. 2011 Mar 29; 108 (13) :5260-5.

Schroer MA, Paulus M, Jeworrek C, Krywka C, Schmacke S, Zhai Y, Wieland DC, Sahle CJ, Chimenti M, Royer CA, Garcia-Moreno B, Tolan M, Winter R. High-pressure SAXS study of folded and unfolded ensembles of proteins. Biophys J. 2010 Nov 17; 99 (10) :3430-7.

Karp DA, Stahley MR, García-Moreno B. Conformational consequences of ionization of Lys, Asp, and Glu buried at position 66 in staphylococcal nuclease. Biochemistry. 2010 May 18; 49 (19) :4138-46.

Pey AL, Rodriguez-Larrea D, Gavira JA, Garcia-Moreno B, Sanchez-Ruiz JM. Modulation of buried ionizable groups in proteins with engineered surface charge. J Am Chem Soc. 2010 Feb 3; 132 (4) :1218-9.

Pais TM, Lamosa P, Garcia-Moreno B, Turner DL, Santos H. Relationship between protein stabilization and protein rigidification induced by mannosylglycerate. J Mol Biol. 2009 Nov 27; 394 (2) :237-50.

Garcia-Moreno B. Adaptations of proteins to cellular and subcellular pH. J Biol. 2009; 8 (11) :98.

Mitra L, Rouget JB, Garcia-Moreno B, Royer CA, Winter R. Towards a quantitative understanding of protein hydration and volumetric properties. Chemphyschem. 2008 Dec 22; 9 (18) :2715-21.

Isom DG, Cannon BR, Castañeda CA, Robinson A, García-Moreno B. High tolerance for ionizable residues in the hydrophobic interior of proteins. Proc Natl Acad Sci U S A. 2008 Nov 18; 105 (46) :17784-8.

Takayama Y, Castañeda CA, Chimenti M, García-Moreno B, Iwahara J. Direct evidence for deprotonation of a lysine side chain buried in the hydrophobic core of a protein. J Am Chem Soc. 2008 May 28; 130 (21) :6714-5.

Harms MJ, Schlessman JL, Chimenti MS, Sue GR, Damjanovic A, García-Moreno B. 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. 2008 May; 17 (5) :833-45.

Matousek WM, Ciani B, Fitch CA, Garcia-Moreno B, Kammerer RA, Alexandrescu AT. Electrostatic contributions to the stability of the GCN4 leucine zipper structure. J Mol Biol. 2007 Nov 16; 374 (1) :206-19.

Brun L, Isom DG, Velu P, García-Moreno B, Royer CA. Hydration of the folding transition state ensemble of a protein. Biochemistry. 2006 Mar 21; 45 (11) :3473-80.

Damjanovic A, García-Moreno B, Lattman EE, García AE. Molecular dynamics study of water penetration in staphylococcal nuclease. Proteins. 2005 Aug 15; 60 (3) :433-49.

García-Moreno B, Dwyer JJ, Gittis AG, Lattman EE, Spencer DS, Stites WE. Experimental measurement of the effective dielectric in the hydrophobic core of a protein. Biophys Chem. 1997 Feb 28; 64 (1-3) :211-24.

Meeker AK, Garcia-Moreno B, Shortle D. Contributions of the ionizable amino acids to the stability of staphylococcal nuclease. Biochemistry. 1996 May 21; 35 (20) :6443-9.