 |
Jerome Baudry UT/ORNL Center for Molecular Biophysics |
Keywords:
Molecular modeling, computational chemistry, molecular biophysics, computational biology, molecular dynamics, drug discovery, drug design, structure function relationships.
Research Area:
The study of regulatory proteins within the human circulatory system that control a variety of processes, including formation/lysis of blood clots and aspects of humoral immunity and wound healing.
Description of Research:
The Baudry laboratory uses molecular modeling and computational chemistry to investigate how bio-molecules interact with each other. We are particularly interested in molecular discovery, i.e. how to select and/or design small molecules, like pharmaceuticals, that will interact in a specific and potent way with much larger molecules, like proteins. Small molecules may sometimes enhance, or sometimes inhibit, the functioning of the proteins to which they bind. To understand protein /ligand interactions we must know and understand a great deal about a particular protein, such as where are possible cavities in the protein, how do these cavities moves and change their shapes with time, and what are the side chains that define these cavities: are residues there neutral, charged, small, large, resonant etc… Molecular modeling allows such very detailed atomic-scale investigations. Drug discovery is the discovery and understanding of the atomic details that will allow small molecules to be perfectly happy, in a thermodynamic way, inside the binding sites of their target proteins. The Baudry lab is involved in structure-based molecular discovery on a variety of targets, such as cytochrome P450s, cancer targets, or hormone or antibiotic receptors, among others. In these projects we collaborate with various experimental groups to synthesize, screen, and test the small molecules for desired biological activity. In addition we are actively developing methods and protocols to accelerate computer-aided drug discovery and drug design.
We are also actively involved in a more fundamental approach to protein dynamics and ligand/protein interactions. We are investigating the dynamics of methyl groups in proteins and molecular crystals. Methyl groups, such as the side chain of alanine, are widely found in proteins and their rotations are very sensitive to the local microenvironment. Variation in methyl rotational dynamics is being recognized as a very important contribution to the thermodynamic of proteins and of protein/ligand interactions. We use theoretical methods to identify methyl groups in protein and molecular crystals that will undergo changes in their rotational dynamics upon ligand binding or micro-environmental variations, and we study how these changes are coupled with the functioning of the protein and the ligand binding. These studies have allowed us to extend our research in frontier domains such as solid-state and surface chemistry, and bio-nano technologies.
Selected Publications:
- Biasing Reaction Pathways with Mechanical Force. C. R. Hickenboth, J.S. Moore, S.R. White, N. R. Sottos, J. Baudry, and S.R. Wilson Nature, (2007) 446:423-427
- van der Waals Interactions and Decrease of the Rotational Barrier of Methyl-size Rotators: A Theoretical Study. J. Baudry J. Am. Chem. Soc. (2006) 128(34):11088-11093
- Class-Dependent Sequence Alignment Strategy Improves the Structural and Functional Modeling of P450s. J. Baudry, S. Rupasinghe, and M. Schuler Protein Eng. Des. Sel. (2006) 19(8):345ñ353
- Can Proteins and Crystals Self-Catalyze Methyl Rotations? J. Baudry and J.C. Smith J. Phys. Chem. B. (2005) 109:20572-20578
- Structure-based Design and In-Silico Virtual Screening of combinatorial Libraries. A Combined Chemical/Computational Assignment. J. Baudry and P. Hergenrother J. Chem. Edu. (2005) 82(6):890-894