The research in my laboratory is focused on molecular modeling as an approach to studying protein structure and function. For example, we are studying the β-glucosidases, which are enzymes that occur in all living organisms. Although much is known about the mechanism of catalysis by β-glucosidases, there is virtually no information as to how β-glucosidases recognize and interact with their substrates. In this regard, we are applying computer-based molecular docking to understand better the subtle substrate specificity differences among β-glucosidases.

We are also investigating proteins related to neurodegeneration, specifically monoamine oxidase B (MAOB) and the amyloid β-peptide (Aβ), which have been implicated in diseases such as Parkinson's disease and Alzheimer's disease. MAOB is an enzyme that oxidizes neurotransmitters and some dietary compounds so that they may be recycled or excreted from the body. As a result of this process, hydrogen peroxide is produced, causing oxidative stress on the brain. Several MAOB inhibitors have been designed to bind to the protein, blocking its action and blocking the production of hydrogen peroxide, and have been used to help slow the progression of the Parkinsonian-type symptoms related to Parkinson's disease. However, these drugs interact with other proteins, causing unfavorable side effects, so the search continues for more specific and better drugs. The active site of MAOB has previously been identified; however, we are only very recently beginning to understand why certain drugs bind more often and more specifically than other drugs. Of the 16,500 atoms that comprise the MAOB protein, our lab has pinpointed approximately 20 atoms that play an important role in the drug binding process.

The amyloid β-peptide (Aβ) has been identified as the core component of protein aggregates in the brains of Alzheimer's patients. The pathway by which Aβ leaves the cell membrane and self-associates is largely a mystery, and we are applying molecular dynamics (MD) simulations to study this pathway and gain insight on details that are hidden from most experimental techniques. Also of interest in this project is the association of Aβ and oxidative stress. Alzheimer's patients suffer from extensive oxidative damage to brain tissue, believed to be caused by Aβ. Experimental work has identified dietary compounds that may bind to Aβ and inhibit the damaging effects of this peptide. Simulations will focus on understanding this effect, with the goal of designing effective small molecule inhibitors of Aβ aggregation. We are working to extend existing force field parameter sets to include the small molecules of interest to expand upon the data from in vitro studies.

Kittur, F.S., Yu, H.Y., Bevan, D.R., and Esen, A. (2010) Deletion of the N-terminal Dirigent Domain in Maize beta-Glucosidase Aggregating Factor and its Homolog Sorghum Lectin Dramatically Alters the Sugar-specificities of Their Lectin Domains. Plant Physiol. Biochem. 48: 731-734.

Lu, P., Bevan, D.R., Lewis, S.N., Hontecillas, R., and Bassaganya-Riera, J. (2010) Molecular Modeling of Lanthionine Synthetase Component C-like Protein 2: A Potential Target for the Discovery of Novel Type 2 Diabetes Prophylactics and Therapeutics. J. Mol. Model., in press.

Lemkul, J.A. and Bevan, D.R. (2010) Assessing the Stability of Alzheimer's Amyloid Protofibrils Using Molecular Dynamics. J. Phys. Chem. B 114: 1652-1660.

Lemkul, J.A. and Bevan, D.R. (2010) Destabilizing Alzheimer's A-beta42 Protofibrils with Morin: Mechanistic Insights from Molecular Dynamics Simulations. Biochemistry 49: 3935-3946.

Lewis, S.N., Bassaganya-Riera, J., and Bevan, D.R. (2010) Virtual Screening as a Technique for PPAR Modulator Discovery. PPAR Research 10pp. doi:10.1155/2010/861238.

Allen, W.J., Capelluto, D.G.S., Finkielstein, C.V., and Bevan, D.R. (2010) Modeling the Relationship between the p53 C-terminal Domain and its Binding Partners Using Molecular Dynamics. J. Phys. Chem. B 141: 13201-13213.

Yu, H.Y., Kittur, F.S., Bevan, D.R., and Esen, A. (2009) Determination of beta-Glucosidase Aggregating Factor (BGAF) Binding and Polymerization Regions on the Maize beta-Glucosidase Isozyme Glu1. Phytochemistry 70: 1355-1365.

Lemkul, J.A. and Bevan, D.R. (2009) Perturbation of Membranes by the Amyloid beta-Peptide --- A Molecular Dynamics Study. FEBS J. 276: 3060-3075.

Liu, W., Hong, J., Bevan, D.R., and Zhang, Y.-H. P. (2009) Fast Identification of Thermostable beta-Glucosidase Mutants on Cellobiose by a Novel Combinatorial Selection/Screening Approach. Biotechnol. Bioeng. 103: 1087-1094 .

Allen, W.J., Lemkul, J.A., and Bevan, D.R. (2009) GridMAT-MD: A Grid-based Membrane Analysis Tool for use with Molecular Dynamics. J. Comput. Chem. 30: 1952-1958.