Faculty Profile

Faculty Profile of Michael Brown

Michael Brown


Email: mfbrown@email.arizona.edu
Building: OC 228
Phone: 520-621-2163


  • Japan Society for the Promotion of Science Research Fellowship, 2003-04
  • Senior Fullbright Fellow (Italy), 2000-01
  • Roentgen-Professorship of Physics (Germany), 1999
  • The Wilhelm Conrad Roentgen Lecture (University of WΓΌrzburg), 1999
  • NIH Research Career Development Award, 1985-90
  • Alfred P. Sloan Foundation Research Fellowship, 1983-85

Education and Appointments

  • A.B. 1970, University of California at Santa Cruz
  • Ph.D. 1975, University of California at Santa Cruz
  • NIH Postdoctoral Fellow 1976-79, Biozentrum of the University of Basel (Switzerland)
  • NIH Postdoctoral Fellow 1979, University of California at Berkeley

Research Interests

  • Biochemistry
  • Physical
  • "Theory, Modeling, and Simulation"
  • Bioanalytical
  • Biophysics
  • Chemical Biology
  • Chemical Physics
  • Instrument Development
  • Protein and Membrane Biochemistry
  • Spectroscopy/molecular Structure
  • Structural Biology
  • Surfaces and Solid State

Research Summary

Physical Chemistry and Biochemistry / Biophysics / Nuclear Magnetic Resonance Spectroscopy / Membranes

Nuclear magnetic resonance (NMR) is the most widely used spectroscopic method in chemistry and biochemistry - there many applications and research opportunities. Applications range from organic synthesis to protein structure elucidation in solution and fibrils or membranes, and to magnetic resonance imaging (MRI) of human subjects. Apart from its remarkable breadth and versatility, a unique feature of NMR is the ability to provide information about both structure and dynamics. Our research entails the development of NMR techniques through applications to materials science and biomolecular systems. A cross-disciplinary approach is taken to relate the properties of materials and molecular structure to function.

Currently, we are actively engaged in research in several interrelated areas. Our aims in spectroscopy and analytical methods entail development and application of NMR methods to liquid-crystalline materials and biomolecular systems. In the area of biophysics, we are conducting structural studies of membrane proteins and membrane lipids. A common theme is to illuminate material or biochemical properties using molecular structural methods that advance our mechanistic understanding for applications. A range of chemical, physical, analytical, and biochemical methods are used, and provide the opportunity for broad-based cross-disciplinary training.

Nuclear Magnetic Resonance (NMR) Spectroscopy. We are currently using powerful NMR methods to investigate molecular solids, liquids, liquid crystals, and membrane materials. Experimental and theoretical NMR methods allow us to investigate the equilibrium structural properties and molecular dynamics. In NMR spectroscopy we observe chemical shift, dipolar interactions, and quadrupolar interactions, and separate them in one, two, or three dimensions. Investigations of aligned samples utilize solid-state NMR methods. Together with magic-angle spinning studies, we obtain the orientational and distance restraints needed for structural determination of non-crystalline materials. NMR relaxation methods are applied to establish the molecular motions that underlie the equilibrium structures. Measurements are conducted for non-crystalline membrane lipids, misfolded protein fibrils, and membrane proteins.

Molecular Structure and Dynamics Using Solid-State NMR. Another major emphasis involves developing solid-state NMR techniques and relaxation theory for the study of molecular solids and liquid crystals. Deuterium (2H) quadrupolar echo spectroscopy is used to characterize the structural properties, relaxation behavior, and molecular dynamics. Our experimental NMR work is complemented by state-of-the-art molecular dynamics (MD) computer simulations. Currently we use the world's second largest supercomputer (Blue Gene, at IBM) for this work. Multidimensional NMR and MD simulations enable us to understand how protein structural and dynamical properties are related to chemical reactivity, and to biological function.

Membrane Receptors, Ion Channels, and Pumps. Applications of molecular spectroscopy to membrane proteins include proteins involved in neuroscience and so-called G protein-coupled receptors (GPCRs). Membrane-associated peptides and integral membrane proteins are receptors for light, hormones, and neurotransmitters. GPCRs are the largest protein family in the human genome, and they play a central role in pharmacology. Ion channels and pumps produce life on Earth and are of phenomenal importance in the energy budget of the planet through energy conversion and photosynthesis. Misfolding of membrane proteins occurs in neurodegeneration, including Parkinson's and Alzheimer's diseases, with profound medical relevance. Proteins are purified from natural sources or expressed using molecular biology techniques. Our structural work involves organic synthesis and isotopic labeling of the ligands for integral membrane proteins in conjunction with NMR spectroscopy. Angular and distance constraints are used for molecular modeling of the protein-bound ligands.

Biochemistry and Biophysics of Membranes. Many scientists believe that we live in a protein-centered universe. However, some of us now recognize that proteins are significantly affected by membrane lipids as an additional control element. A particularly dramatic example involves the polyunsaturated lipids that play an important role in the nervous system. We have developed a New Biomembrane Model that explains the influences of lipid-protein interactions on biological function in terms of elastic deformation of the membrane lipid film. Activation of membrane proteins is explained at the molecular level in terms of an exotic new concept that we call frustration -- the ligand, the protein, and the membrane lipid bilayer are all tightly coupled. We are currently testing the New Biomembrane Model through studies of rhodopsin. The molecular basis of vision is studied by fast photochemical reaction techniques and biochemical assays. Experimental work in molecular spectroscopy involves three superconducting Fourier transform NMR spectrometers (500, 300, and 200 MHz). Homebuilt high-power probes and other accessories are available for solid-state NMR applications. High-resolution NMR studies are conducted using the University of Arizona NMR facilities, which include two 500 MHz NMR spectrometers and one 600 MHz spectrometer with complete multinuclear capabilities. Our research is highly multidisciplinary, and provides opportunities for graduate training in analytical NMR techniques and optical spectroscopies; instrumentation development; biochemical methods including protein and lipid chemistry; and biotechnology.

Figure 1: Example of NMR spectrometer with superconducting magnet used for our studies of membrane proteins.

Figure 2: Example of two-dimensional solid-state NMR spectrum of a membrane protein. Notice the cross-peaks that provide structural information.

Figure 3: Structure of retinal in binding pocket of rhodopsin established from solid-state NMR and molecular dynamics (MD) computer simulations.

Figure 4: Solid-state NMR structure of retinal bound to rhodopsin in the dark (green) and light (red) states.

Selected Publications

• Petrache, H. I., Dodd, S. W., and Brown, M. F. (2000), Area per Lipid and Acyl Length Distributions in Fluid Phosphatidylcholines Determined by 2H NMR Spectroscopy, Biophys. J. 79, 3172-3192.

• Brown, M. F., Thurmond, R. L., Dodd, S. W.,Otten, D., and Beyer , K. (2001), Composite Membrane Deformation on the Mesoscopic Length Scale, Phys. Rev. E 64, 010901/1-10901/4.

• Petrache, H. I., Salmon, A. S., and Brown, M. F. (2001), Structural Properties of Docosahexaenoyl Phospholipid Bilayers Investigated by Solid-State 2H NMR Spectroscopy, J. Am. Chem. Soc. 123, 12611-12622.

• Huber, T., Rajamoorthi, K., Kurze, V., Beyer, K., and Brown, M. F. (2002), Structure of Docosahexaenoic Acid-Containing Bilayers as Studied by 2H NMR and Molecular Dynamics Simulations, J. Am. Chem. Soc. 124, 298-309.

• Botelho, A. V., Gibson, N. J., Thurmond, R. L., Wang, Y., and Brown, M. F. (2002), Conformational Energetics of Rhodopsin Modulated by Nonlamellar-forming Lipids, Biochemistry 41, 6354-6368.

• Brown, M. F., Thurmond, R. L., Dodd, S. W., Otten, D., and Beyer, K. (2002), Elastic Deformation of Membrane Bilayers Probed by Deuterium NMR Relaxation, J. Am. Chem. Soc. 124, 8471-8484.

• Martinez, G. V., Dykstra, E. M., Lope-Piedrafita, S. Job, C, and Brown, M. F. (2002) NMR Elastometry of Fluid Membranes in the Mesoscopic Regime, Phys. Rev. E 66, 050902/1-050902/4.

• Endress, E., Heller, H., Casalta, H., Brown, M. F., and Bayerl, T. M. (2002), Anisotropic motion and molecular dynamics of cholesterol, lanosterol, and ergosterol in lecithin bilayers studied by quasi-elastic neutron scattering, Biochemistry 41, 13078-13086.

• Wang, Y., Botelho, A. V., Martinez, G. V., and Brown, M. F. (2002), Electrostatic Properties of Membrane Lipids Coupled to Metarhodopsin II Formation in Visual Transduction, J. Am. Chem. Soc. 124, 7690-7701.

• Martinez, G. V., Dykstra, E. M., Lope-Piedrafita, S., and Brown, M. F. (2004), Lanosterol and Cholesterol-Induced Variations in Bilayer Elasticity Probed by 2H NMR Relaxation, Langmuir 20, 1043-1046.

• Huber, T., Botelho, A. V., Beyer, K., and Brown, M. F. (2004), Membrane Model for the GPCR Rhodopsin: Hydrophobic Interface and Dynamical Structure, Biophys. J. 86, 2078-2100.

• Henzler-Wildman, K. A., Martinez, G. V., Brown, M. F., and Ramamoorthy, A. (2004), Perturbation of the Hydrophobic Core of Lipid Bilayers by the Human Antimicrobial Peptide LL-37, Biochemistry 43, 8459-8469.

• Salgado, G. F. J., Struts, A. V., Tanaka, K., Fujioka, N., Nakanishi, K., and Brown, M. F. (2004), Deuterium NMR Structure of Retinal in the Ground State of Rhodopsin, Biochemistry 43, 12819-12828.

• Rajamoorthi, K., Petrache, H. I., McIntosh, T. J., and Brown, M. F. (2005), Packing and Elasticity of Polyunsaturated w-3 and w-6 Phospholipids as Determined by 2H NMR Spectroscopy and X-Ray Diffraction, J. Am. Chem. Soc. 127, 1576-1588.

• Vogel, A., Katzka, C. P., Waldmann, H., Arnold, K., Brown, M. F., and Huster, D. (2005), Lipid Modifications of a Ras Peptide Exhibit Altered Packing and Mobility Versus Host Membrane as Detected by 2H Solid-State NMR, J. Am. Chem. Soc. 127, 12263-12272.

• Subramaniam, V., Alves, I. D., Salgado, G. F. J., Lau, P.-W., Wysocki, Jr., R. J., Salamon, Z., Tollin, G., Hruby, V. J., Brown, M. F., and Saavedra, S. S. (2005), Rhodopsin Reconstituted into a Planar-Supported Lipid Bilayer Retains Photoactivity after Cross-Linking Polymerization of Lipid Monomers, J. Am. Chem. Soc. 127, 5320-5321.

• Alves. I. D., Salgado, G. F. J., Salamon, Z., Brown, M. F., Tollin, G., and Hruby, V. J. (2005), Phosphatidylethanolamine Enhances Rhodopsin Photoactivation and Transducin Binding in a Solid-Supported Lipid Bilayer as Determined Using Plasmon-Waveguide Resonance Spectroscopy, Biophys. J. 88, 198-210.

• Salgado, G. F. J., Struts, A. V., Tanaka, T., Krane, S., Nakanishi, K., and Brown, M. F. (2006), Solid-State 2H NMR Spectroscopy of Retinal Cofactor of Metarhodopsin I, J. Am. Chem. Soc. 128, 11067-11071.

• Botelho, A. V.. Huber, T., Sakmar, T. P., and Brown, M. F. (2006), Curvature and Hydrophobic Forces Drive Constitutive Association and Modulate Activity of Rhodopsin in Membranes, Biophys. J 91, 4464-4477.

• MartΓ­nez-Mayorga, K., Pitman, M. C., Grossfield, A., Feller, S. E., and Brown, M. F. (2006), Retinal Counterion Switch Mechanism in Vision Evaluated by Molecular Simulations, J. Am. Chem. Soc 28; 16502-16503.

• Struts, A. V., Salgado, G. F. J., Fujioka, N., Nakanishi, K., and Brown, M. F. (2007), Retinal Conformation and Orientation in the Dark State of Rhodopsin Elucidated by Solid State 2H NMR, J. Mol. Biol., in press.

• Vogel, A., Tan, K.-T, Waldmann, H., Feller, S. E., Brown, M. F., and Huster, D. (2007), Flexibility of Ras Lipid Modifications Studied by 2H Solid-State NMR and Molecular Dynamics Simulations, Biophys. J., in press.

• Lau, P.-W., Grossfield, A., Feller, S. E., Pitman, M. C., and Brown, M. F. (2007), Dynamic Structure of Retinylidene Ligand of Rhodopsin Probed by Molecular Simulations, J. Mol. Biol., in press.