- B.S., Old Dominion University (Biology)
- Ph.D., Virginia Commonwealth University (Pharmaceutical Sciences)
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.
Since 2007, 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; http://www.ccbb.pitt.edu/). 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, 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.
1. Kellogg, G.E.; Scarsdale, J.N.; Cashman, D.J. (1999) Ligand Docking and Scoring in DNA Oligonucleotides. Binding of Doxorubicin and Modeled Analogs to Optimize Sequence Specificity. Medicinal Chemistry Research, Vol. 9, No. 7/8, 592 - 603.
2. Cashman, D.J.; Rife, J.P.; Kellogg, G.E. (2001) ">Which Aminoglycoside Ring Is Most Important For Binding? A Hydropathic Analysis of Gentamicin, Paromomycin, and Analogues. Bioorganic & Medicinal Chemistry Letters, Vol. 11, 119 - 122.
3. Cashman, D.J.; Scarsdale, J.N.; Kellogg, G.E. (2003) Hydropathic Analysis of the Free Energy Differences in Anthracycline Antibiotic Binding to DNA. Nucleic Acids Research, Vol. 31, No. 15, 4410 - 4416.
4. Cashman, D.J. & Kellogg, G.E. (2004) A Computational Model for Anthracycline Antibiotic Binding to DNA: Tuning Groove-Binding Intercalators for Specific Sequences. Journal of Medicinal Chemistry, Vol. 47, 1360 - 1374.
5. Cashman, D.J.; Rife, J.P.; Kellogg, G.E. (2004) Docking and Hydropathic Analysis of Hoechst 33258 with Double-Stranded RNA. Medicinal Chemistry Research, Vol. 12, No. 8, 445 - 455.
6. Portugal, J.; Cashman, D.J.; Trent, J.O.; Ferrer-Miralles, N.; Przewloka, T.; Fokt, I.; Priebe, W.; Chaires, J.B. (2005) A New Bisintercalating Anthracycline with Picomolar DNA Binding Affinity. Journal of Medicinal Chemistry, Vol. 48, 8209 - 8219.
7. Freyer, M.W.; Buscaglia, R.; Cashman, D.J.; Hyslop, S.; Wilson, W.D.; Chaires, J.B. Lewis, E.A. (2006) Binding of Netropsin to Several DNA Constructs: Evidence For at Least Two Different 1:1 Complexes Formed From an -AATT-containing ds-DNA Construct and a Single Minor Groove Binding Ligand. Biophysical Chemistry, Vol. 126, 186 - 196.
8. Freyer, M.W.; Buscaglia, R.; Kaplan, K.; Cashman, D.J.; Hurley, L.H.; Lewis, E.A. (2007) Biophysical Studies of the c-MYC NHE-III1 Promoter: Model Quadruplex Interactions with a Cationic Porphyrin. Biophysical Journal, Vol. 92, 2007 - 2015.
9. Cashman, D.J.; Freyer, M.W.; Dettler, J.M.; Hurley, L.H.; Lewis, E.A. (2008) Molecular Modeling and Biophysical Analysis of the c-MYC NHE-III1 Silencer Element. Journal of Molecular Modeling, Vol. 14, No. 2, 92 - 101.
10. Mamonov, A.B.; Bhatt, D.; Cashman, D.J.; Ding, Y.; Zuckerman, D.M. (2009) A Library-Based Monte Carlo Technique Enables Rapid Equilibrium Sampling of a Protein Model with Atomistic Components. J. Phys. Chem. B, Vol. 113, No. 31, 10891 - 10904.
11. Dettler, J.; Buscaglia, R.; Cui, J.-J.; Cashman, D.J.; Blynn, M.; Lewis, E.A. (2010) Biophysical Characterization of an Ensemble of Intramolecular i-Motifs Formed by the Human c-MYC NHE-III1 P1 Promoter Mutant Sequence. Biophysical Journal, Vol. 99, Issue 2, 561-7.
12. Cashman, D.J.; Mamonov, A.B.; Bhatt, D.; Zuckerman, D.M. (January 2011) Thermal Motions of the E. Coli Glucose-Galactose Binding Protein Studied Using Well-Sampled Semi-Atomistic Simulations. Current Topics in Medicinal Chemistry, Vol. 11, No. 2, 211-220.
13. Cashman, D.J.; Ortega, D.R.; Zhulin, I.B.; Baudry, J. (2013) Homology Modeling of the CheW Coupling Protein of the Chemotaxis Signaling Complex. PLOS ONE, Vol. 8, No. 8, e70705.
14. Cashman, D.J.; Zhu, T.; Simmerman, R.S.; Scott, C.; Bruce, B.D.; Baudry, J. (2014) Molecular Interactions Between Photosystem I and Ferredoxin: An Integrated Energy Frustration and Experimental Model. Accepted for Publication in the Journal of Molecular Recognition.
15. Cashman, D.J.; McBride, T.S.; Zhulin, I.B.; Baudry, J. (2013) Rigid Body Docking Studies of Bacterial Chemotaxis Proteins Based on Energy Landscape Analysis. Manuscript in Preparation.