Ashley Spies

Ashley Spies

  • Associate Professor, Department of Pharmaceutical Sciences and Experimental Therapeutics / Division of Medicinal and Natural Products Chemistry

Office

S313 PHAR

Phone

(319) 335-5645

Research Narrative

Our research group investigates the fundamental properties of protein-ligand interactions, from a physical and chemical perspective. Our primary focus is on pharmaceutically relevant enzymes. The application and development of computational chemistry often plays a central role in addressing research questions centering on the discovery and design of novel ligands to validated drug targets. Computational insights are bolstered by in vitro and in vivo assays. Ongoing projects include: i) development of parallelized in silico docking using high performance computing (HPC) on the University of Iowa's Helium cluster, ii) use of steered molecular dynamics to perform highly accurate and precise free energy calculations to accurately rank order drug leads to a number of antimicrobial and antineoplastic targets, iii) use of hybrid QM/MM electronic structure methods to understand remote allosteric modulation of enzyme catalytic power.

Curriculum vitae

Education
BS, University of Kansas, 1991
PhD, University of Kansas, 1997

Professional Experience
1997 - 2000, Postdoc, Institute for Scientific and Industrial Research (SANKEN), Osaka University, Osaka, Japan
2000 - 2005, Postdoc, University of California, Davis
2005 – 2012, Research Assistant Professor, Department of Biochemistry, University of Illinois, Urbana-Champaign
2012 – present, Assistant Professor of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa, and Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, Iowa

Awards
JSPS (Japanese Ministry of Science) Postdoctoral Fellowship, 1998

Research Interests
Our research group investigates the fundamental properties of protein-ligand interactions, from a physical and chemical perspective. Our primary focus is on pharmaceutically relevant enzymes. The application and development of computational chemistry often plays a central role in addressing research questions centering on the discovery and design of novel ligands to validated drug targets. Computational insights are bolstered by in vitro and in vivo assays. Ongoing projects include: i) development of parallelized in silico docking using high performance computing (HPC) on the University of Iowa's Helium cluster, ii) use of steered molecular dynamics to perform highly accurate and precise free energy calculations to accurately rank order drug leads to a number of antimicrobial and antineoplastic targets, iii) use of hybrid QM/MM electronic structure methods to understand remote allosteric modulation of enzyme catalytic power and iv) development of cheminformatics tools for parsing attractive regions of chemical space in screening libraries.

Recent Publications

Dean, S.F., Whalen, K.L., Spies, M.A. Biosynthesis of a Novel Glutamate Racemase Containing a Site-Specific 7-Hydroxycoumarin Amino Acid: Enzyme–Ligand Promiscuity Revealed at the Atomistic Level. 2015, ACS Central Science Article ASAP. DOI: 10.1021/acscentsci.5b00211.

Whalen, K.L., Spies, M.A. Flooding enzymes: quantifying the contributions of interstitial water and cavity shape to ligand binding using extended linear response free energy calculations. 2013, J Chem Inf Model. 53(9):2349-59. PubMed PMID: 24111836.

Subramanyam, S., Jones, W.T., Spies, M., Spies, M.A. Contributions of the RAD51 N-terminal domain to BRCA2-RAD51 interaction. 2013, Nucleic Acids Res. 41(19):9020-32. PubMed PMID: 23935068.

Whalen, K.L., Chau, A.C., Spies, M.A. In silico Optimization of a Fragment-Based Hit Yields Biologically Active, High-Efficiency Inhibitors for Glutamate Racemase. 2013, ChemMedChem. 8(10):1681-1689. PubMed PMID: 23929705.

Whalen, K.L., Chang, K., Spies, M.A. Hybrid Steered Molecular Dynamics-Docking: an efficient solution to the problem of ranking inhibitor affinities against a flexible drug target. 2011, Molecular Informatics. 30(5): 459–471. PMCID: PMC3129543.

Whalen, K.L., Tussey, K.B., Blanke, S.R., Spies, M.A. Nature of Allosteric Inhibition in Glutamate Racemase: Discovery and Characterization of a Cryptic Inhibitory Pocket using Atomistic MD Simulations and pKa Calculations. 2011, J. Phys. Chem. B. 115(13):3416-24. PMID: 21395329.

Whalen, K.L., Pankow, K.L., Blanke, S.R., Spies, M.A. Exploiting Enzyme Plasticity in Virtual Screening: High Efficiency Inhibitors of Glutamate Racemase. 2010, ACS Med. Chem. Lett. 1, (1) 9-13. PMID: 20634968.

Lin, L.J., Yoshinaga, A., Lin, Y., Guzman, C., Chen, Y.H., Mei, S., Lagunas, A.M., Koike, S., Iwai, S., Spies, M.A., Nair, S.K., Mackie, R.I., Ishino, Y., Cann, I.K. Molecular analyses of an unusual translesion DNA polymerase from Methanosarcina acetivorans C2A. 2010, J. Mol. Biol. 397 (1) 13-30.

Spies, M.A., Reese, J.G., Dodd, D., Pankow, K.L., Blanke, S.R., Baudry, J. Determinants of Catalytic Power and Ligand Binding in Glutamate Racemase. 2009, J. Am. Chem. Soc. 131(14):5274-84.

Dodd, D., Kocherginskaya, S.A., Spies, M.A., Beery, K.E., Abbas, C.E., Mackie, R.I., Cann, I.K.O Biochemical Analysis of a β-D-xylosidase and a Bifunctional 1 Xylanase-Ferulic Acid Esterase from a Xylanolytic Gene Cluster in Prevotella ruminicola 23. 2009, J. Bacteriol. 191(10):3328-38.

Bae, B., Ohene-Adjei, S., Kocherginskaya, S., Mackie, R.I., Spies, M.A., Cann, I.K.O., and Nair, S.K. Molecular Bases for the Promiscuity and Specificity of Ligand Recognition by the Carbohydrate Binding Modules from Thermoanaerobacterium polysaccharolyticum manA. 2008, J. Biol. Chem. 283(18): 12415-25.

Spies, M.A. and Toney, M.D. Intrinsic Primary and Secondary Hydrogen Kinetic Isotope Effects for Alanine Racemase from Global Analysis of Progress Curves. 2007, J. Am. Chem. Soc. 129(35):10678-85.

Moore, R.H., Spies, M.A., Culpepper, M.B., Murakawa, T., Hirota, S., Okajima, T., Tanizawa, K. and Mure, M. Trapping of a Dopaquinone Intermediate in the TPQ Cofactor Biogenesis in a Copper-containing Amine Oxidase from Arthrobacter globiformis. 2007, J. Am. Chem. Soc. 129(37):11524-34.
 
Dodd, D., Reese, J.G., Louer, C.R., Ballard, J.D., Spies, M.A., Blanke, S.R. Functional Comparison of the Two Bacillus Anthracis glutamate racemases. 2007, J Bacteriol. 189(14):5265-75.

Cann, I.K.O., Dodd, D., Nair, S. K., Mackie, R. I., and Spies, M. A. Bacterial genome mining to advance enzymology for plant cell wall degradation. (Invited Review). The 7th International Symposium on the Nutrition of Herbivores (ISNH-7). 2007, Beijing, China.

Spies, M.A. and Toney, M.D. Multiple Hydrogen Transfers in Enzyme Action in Hydrogen-Transfer Reactions. Volume 3, 1139-1170 (Eds. J.P. Klinman and R.L. Schowen), (2006) Wiley-VCH Verlag GmbH, Weinheim.

Spies, M.A., Woodward, J.J., Watnik, M.R., and Toney, M.D. Alanine Racemase Free Energy Profiles from Global Analysis of Progress Curves. 2004, J. Am. Chem. Soc., 126:7464-75.

Christenson, S.D., Weiming, W., Spies, M.A., Shen, B., and Toney, M.D. Kinetic Analysis of the 4-Methylideneimidazole-5-one-Containing Tyrosine Aminomutase in Enediyne Antitumor Antibiotic C-1027 Biosynthesis. 2003, Biochemistry, 42(43):12708-18.

Spies, M.A. and Toney, M.D. Multiple Hydrogen Kinetic Isotope Effects for Enzymes Catalyzing Exchange with Solvent: Application to Alanine Racemase. 2003, Biochemistry, 42, 5099-5107.

Spies, M.A. and Schowen, R.L. Τhe Trapping of a Spontaneously “Flipped-Out” Base from Double Helical Nucleic Acids by Host-Guest Complexation with β-Cyclodextrin: the Intrinsic Base-Flipping Rate Constant for DNA and RNA. 2002, J. Am. Chem. Soc. 124, 14049-14053.

Takusagawa, F., Fujioka, M., Spies, M.A. and Schowen, R.L., S-Adenosylmethionine (AdoMet)-dependent Methyltransferases, in Comprehensive Biological Catalysis, ed. Sinnott, M.L., Academic Press, London, 1998: volume 1, 1-30.

Chen, Z., Spies, M.A., Hein, R., Zhou, X., Thomas, B.C., Richter, M.L., and Gegenheimer, P.A. A Subunit Interaction in Chloroplast ATP Synthase Determined by Genetic Complementation Between Chloroplast and Bacterial ATP Synthase Genes. 1995, J. Biol. Chem., 270 (29): 17124-32.