The overall goal of the research in our laboratory is to relate the three-dimensional structure and dynamics of proteins to their biological functions. We use techniques of X-ray crystallography and electron microscopy to elucidate the molecular structures of proteins. Extensive use is made of modern computational methods to analyze the structures and their dynamics.
One research effort is directed toward elucidating the precise molecular mechanisms of the regulation of muscle contraction. The proteins which are involved in the regulatory process have been identified and include: tropomyosin, a highly helical molecule that s filaments wound around actin, and troponin, a complex consisting of three polypeptide chains, that binds to tropomyosin. Detailed information about the structure of these proteins is necessary before their roles in regulation can be understood. We are also interested in the recognition of calcium by muscle proteins, and have studied mutants of parvalbumin to dissect the physical chemical principles involved in calcium signalling. The technique best suited for obtaining this information is X-ray crystallography.
Another project we have underway is directed towards obtaining an atomic description of the basis for binding of oxygen and other ligands to myoglobin. Detailed three-dimensional structures are being determined for native and mutant myoglobins with various ligands bound to the protein. We are moving towards a quantitative understanding of the engineering of heme proteins. The work is being extended to hemoglobin as potential cell-free blood substitute.
Organisms have proteins that are highly adapted to the growing conditions in the environment. We have determined structures of enzymes from hyperthermophilic bacteria to reveal aspects of the connections of protein structure to dynamics, which is an integral part of proteins' designs.
We are also working to develop new techniques for observing the dynamics of proteins and nucleic acids using diffuse X-ray scattering analysis and molecular dynamics simulations. The result will be a transition from "snapshots" of macromolecules to the generation of "movies" of molecules in action.
A new direction in our studies includes computational biology. In particular, the use of modern algorithms from computer science and applied mathematics to solve interesting biological problems.
Click on the links below to view web-based papers:
- The Molecular Structure of Green Fluorescent Protein
- Analysis of Diffuse Scattering from Yeast Initiator tRNA Crystals
- Cross Validation Tests of Time-Averaged Molecular Dynamics Refinements for Determination of Protein Structures by X-Ray Crystallography
- Visualization of Dyanmic Simulations of Muscle Thin Filaments
- A Cellular Automaton Model for the Regulatory Behavior of Muscle Thin Filaments
- Cellular Automata Simulation of Muscle Regulation
- XRayView: A Teaching Aid for X-Ray Crystallography
Click on the links below to view PDF papers:
- Mechanism of NO-Induced Oxidation of Myoglobin and Hemoglobin
- Real-Space Envelopes by the Connectivity Constraint: An Approach to the Ab initio Macromolecular Phase Problem
- High Resolution Crystal Structures of the Deoxy, Oxy, and Aquomet Forms of Cobalt Myoglobin
- Kinetic Pathways and Barriers for Ligand Binding to Myoglobin
- Myoglobin discriminates between O2, NO, and CO by electrostatic interactions with the bound ligand
- Crystal Structures of Bacillus stearothermophilus Adenylate Kinase With Bound Ap5A, Mg2+ Ap5A, and Mn2+ Ap5A Reveal an Intermediate Lid Position and Six Coordinate Octahedral Geometry for Bound Mg2+ and Mn2+
- The Molecular Structure of Green Fluorescent Protein
- Nitric Oxide Myoglobin: Crystal Structure and Analysis of Ligand Geometry
- Solution and Crystal Structure of a Sperm Whale Myoglobin Triple Mutant That Mimics the Sulfide-binding Hemoglobin from Lucina pectinata
- Effects of the Location of Distal Histidine in the Reaction of Myoglobin with Hydrogen Peroxide
- Crystal Structure of Tropomyosin at 7 Ångstroms Resolution
- Protein-Assisted Pericyclic Reactions: An Alternate Hypothesis for the Action of Quantal Receptors
- Conformational Variation of Calcium-Bound Troponin C
- Bound CO is a Molecular Probe of Electrostatic Potential in the Distal Pocket of Myoglobin
- Protein Structure Determination Using a Database of Interatomic Distance Probabilities
- Crystal Structure of a Nonsymbiotic Plant Hemoglobin
- Waterproofing the Heme Pocket
- How the CO in Myoglobin Acquired Its Bend: Lessons in Interpretation of Crystallographic Data
- Molecular Strucutre of Dihydroorotase: A Paradigm For Catalysis Through the Use of a Binuclear Metal Center
- Singular Value Decomposition of Protein Conformational Motions: Applications to HIV-1 Protease
- A Fast Newton Algorithm for Entropy Maximization in Phase Determination
- The Development of the GCPCC Protein Crystallography Beamline at CAMD
- Molecular Mechanisms of Calcium and Magnesium Binding to Parvalbumin
- Structure of an Anti-HIV Monoclonal Fab Antibody Fragment Specific to a gp120 C-4 Region Peptide
- A Fast Newton Method For Entropy Maximization in Statistical Phase Estimation
- Molecular Docking: A Problem With Thousands of Degrees of Freedom
- Probing Substates in Sperm Whale Myoglobin Using High-Pressure Crystallography
- Dynamics of Proteins in Crystals: Comparison of Experiment with Simple Models
- A Dimensionality Reduction Approach to Modeling Protein Flexibility
Click on the MEDLINE search for a listing of publications:
Click on the PDB searches to access the coordinates of structures determined in my laboratory: