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.

Harkcom, W.T. and Bevan, D.R. (2007) Molecular Docking of Inhibitors into Monoamine Oxidase B. Biochem. Biophys. Res. Commun. 360: 401-406.

Ahn, Y.O., Zheng, M., Winkel, B., Bevan, D. R., Esen, A., Shin-Han, S., Benson, J., Peng, H., Miller, J.T., Cheng, C., Poulton, J.E., and Shih, M. (2007) Functional genomic analysis of Arabidopsis thaliana Glycoside Hydrolase Family 35. Phytochem. 68: 1510-1520.

Kittur, F.S., Lalgondar, M., Yu, H.Y., Bevan, D.R., and Esen, A. (2007) Maize β-Glucosidase Aggregating Factor (BGAF) is a Polyspecific Jacalin-Related Chimeric Lectin and Its Lectin Domain is Responsible for beta-Glucosidase Aggregation. J. Biol. Chem. 282: 7299-7311.

Pathange, L.P., Bevan, D.R., Larson, T.J., and Zhang, C. (2006) Correlation Between Protein Binding Strength on Immobilized Metal Affinity Chromatography and the Histidine-Related Protein Surface Structure: The Effect of Surface Accessibility of Histidine Residue and its Involvement in Intramolecular Interactions. Anal. Chem. 78: 4443-4449.

Dana, C.D., Bevan, D.R., and Winkel, B.S.J. (2006) Molecular Modeling of the Effects of Mutant Alleles on Chalcone Synthase Protein Structure. J. Mol. Model. 12: 905-914.

Bevan, D.R., Garst, J.F., Osborne, C.K., and Sims, A.M. (2005) Application of Molecular Modeling to Analysis of Inhibition of Kinesin Motor Proteins of the BimC Subfamilty by Monastrol and Related Compounds. Chem. Biodiversity 2: 1525-1532.

Verdoucq, L., Moriniere, J., Bevan, D.R., Esen, A., Vasella, A., Henrissat, B., and Czjzek, M. (2004) Structural Determinants of Substrate Specificity in Family 1 beta-Glucosidases: Novel Insights from the Crystal Structure of Sorghum Dhurrinase-1, a Plant beta-Glucosidase with Strict Specificity, in Complex with its Natural Substrate. J. Biol. Chem. 279: 31796-31803.   [Abstract]

Xu, Z., Escamilla-Trevino, L.L., Zeng, L., Lalgondar, M., Bevan, D.R., Winkel, B.S.J., Mohamed, A., Cheng, C.-L., Shih, M.-C., Poulton, J.E., and Esen, A. (2004) Functional Genomic Analysis of Arabidopsis thaliana Glycoside Hydrolase Family 1. Plant Mol. Biol. 55: 343-367.

Verdoucq, L., Czjzek, M., Moriniere, J., Bevan, D.R., and Esen, A. (2003) Mutational and Structural Analysis of Aglycone Specificity in Maize and Sorghum beta-Glucosidases. J. Biol. Chem. 278, 25055-25062.