Derek J. Cashman, Ph.D.


B.S., 1995, Old Dominion University (Major: Biology, Minor: Chemistry)

Ph.D., 2003, Virginia Commonwealth University (Pharmaceutical Sciences, Concentration in Medicinal Chemistry)


Research Positions

James Graham Brown Cancer Center, University of Louisville (J. Brad Chaires, Ph.D.) — 2004-2005

Department of Chemistry & Biochemistry, Northern Arizona University (Edwin A. Lewis, Ph.D.) — 2005-2007

Department of Computational & Systems Biology, University of Pittsburgh (Daniel M. Zuckerman, Ph.D.) — 2007-2010

Department of Biochemistry & Cellular & Molecular Biology, University of Tennessee at Knoxville and Center for Molecular Biophysics, Oak Ridge National Laboratory (Jeromy Baudry, Ph.D.) — 2011-2013

Department of Chemistry, Tennessee Technological University — 2013-present



Dr. Cashman's background is in the realm of Computational Biology and Medicinal Chemistry, specializing in the structure-based drug design and molecular simulations of proteins and nucleic acids. He has specific expertise in virtual screening, docking and scoring, molecular mechanics & dynamics, and Monte Carlo simulations. He is also particularly interested in studying protein flexibility and its implications in structure-based drug design and protein-protein interactions.

From 2007 to 2013, he has been engaged in two NIH-funded research projects studying proteins involved in the bacterial chemotaxis pathway. The chemotaxis system of bacteria represents the best studied signal transduction pathway in biology today. This pathway allows bacteria to detect external stimuli via chemoreceptors in the cell membrane and to control the cell’s swimming behavior through phosphorylation of a response regulator protein by a histidine protein kinase. This pathway has been studied for many years, providing a wealth of structural, biochemical, and genetic information. However, many important questions about the system remain unanswered: how the signaling complex is assembled, for example: how signals are terminated, and how covalent modification of receptors contributes to adaptation. Understanding this pathway if of particular interest to medicinal chemists in that the results gained from modeling these proteins will be useful in identifying targets for new therapeutic agents against pathogenic bacteria.

Dr. Cashman's research conducted at the University of Pittsburgh focused on computational simulations of the E. coli Glucose-Galactose Chemosensory Receptor (GGBP), a 309-residue, 32 kDa, periplasmic binding protein consisting of two structural domains. This protein's fluctuations were studied with two computational simulation methods: all-atom molecular dynamics, as well as an extremely fast, "semi-atomistic" Library-Based Monte Carlo (LBMC) method which includes all backbone atoms but "implicit" side chains (open source software developed in the laboratory of Professor Daniel Zuckerman; Both LBMC and MD simulations were performed using both the apo and glucose-bound forms of the protein, with LBMC exhibiting significantly larger fluctuations. The LBMC simulations are in general agreement with the disulfide trapping experiments of Careaga & Falke (J. Mol. Biol., 1992, Vol. 226, 1219-35), which indicate that distant residues in the crystal structure (i.e. beta carbons separated by 10 to 20 angstroms) form spontaneous transient contacts in solution. These simulations illustrate several possible “mechanisms” (configurational pathways) for these fluctuations.

At Oak Ridge National Laboratory (ORNL) his work shifted from the periplasmic space of bacteria, to below the cell membrane, in modeling the structure of the core chemotaxis proteins cheA and cheW and how they interact with the methyl-accepting chemotaxis protein (MCP). The long term goal of this project is to understand how living cells detect, transmit, and adapt to various signals on a molecular level. It involves computational genomic as well as biophysical approaches to understanding three key steps of the bacterial chemotaxis signal transduction pathway: excitation, signal termination, and adaptation. Techniques used include creating a natural classification of chemotaxis proteins based on phylogenetic analysis, identification of conserved residues within evolutionarily related subgroups, co-variance analysis of co-evolving residues, prediction of protein-protein binding sites using computational approaches, and molecular docking simulations to test models of protein-protein interactions.

While working ORNL, he became involved in research in collaboration with Professor Barry Bruce and Jerome Baudry involved in modeling the protein-protein interactions involved in photosystem I with Ferredoxin. Utilizing energetic prediction algorithms embodied in the Protein Frustratometer and Evolutionary Trace, potential docking sites can be predicted on the surface of the proteins. These proteins can be docked using molecular modeling software and the docking can be refined with molecular dynamics calculations on high performance computing clusters. Dr. Cashman is also involved in a similar protein-protein docking study in collaboration with the experimental laboratory of Dr. Xuanzhi (Shawn) Zhan at Tennessee Tech University. This project involves the docking and scoring of Arrestin-3 proteins with JNK3 and G-protein coupled receptors to better understand their mechanisms in the MAPK signal transduction pathway.


Fun and Games

In his free time, Dr. Cashman has a wide variety of interests. He is an avid amateur photographer, shooting with a Nikon D50 DSLR camera. Some of his photography is posted on his Flickr page. Dr. Cashman is also actively involved as an advisor and alumni volunteer in the coeducational National Service Fraternity, Alpha Phi Omega. He enjoys engaging college students in active community service projects and traveling to different campuses presenting leadership development workshops as an APO LEADS presenter. He also enjoys the British science fiction show, Doctor Who, and is an advisor to the Whovian League student organization at Tennessee Technological University.






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