Stefan Paula
Department of Chemistry
Northern Kentucky University
Highland Heights, KY
41099 - 1905
 

E-mail:   paulas1@nku.edu

Research Group

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2000-2004:

Postdoctoral Fellow

University of Cincinnati College of Medicine

1998-2000:

Postdoctoral Fellow / Research Associate

Max Planck Institute for Biochemistry / Martinsried, Germany

1998: 

Ph.D.  University of California at Santa Cruz

1992-1993:

Fulbright Fellow, University of California at Davis

1992:

Diploma in Chemistry, University of Kaiserslautern, Germany

Research Interests

Ligand/Receptor Interactions / Computer-Assisted Drug Design

The primary goal of our research is the study of ligand/receptor interactions on the molecular level using a combination of experimental and computational approaches.  Understanding the factors that determine a protein’s ability to interact specifically with a small molecule is of critical importance for the elucidation of many biological processes as well as for the design of novel drugs.

P-type ATPases are a superfamily of transmembrane proteins that use energy gained from ATP hydrolysis to transport ions across membranes.  Two representatives from this group that are under study are the sodium/potassium ATPase (Na/K-ATPase and the sarco/endoplasmic reticulum calcium ATPase (SERCA).  Na/K-ATPase is inhibited effectively by cardiac glycosides, a class of naturally occurring inhibitors derived from the foxglove plant.  SERCA is inhibited by compounds such as the natural product thapsigargin or derivatives of dibutyl hydroquinones.  To understand the molecular details of inhibition processes, we use a variety of computational approaches.  For instance, the structural components of a compound responsible for effective inhibition can be identified by structure-activity relationship (3D-QSAR) modeling (see figure to the right).  If the three-dimensional structure of the ligand binding site on the receptor is known or can be approximated by homology modeling, inhibitors can be docked computationally into it.  In addition to predicting the biological activity, docking results visualize the orientation of the inhibitor in the binding site (see figure to the right) and thereby reveal the nature and location of crucial ligand/receptor interactions.  The information gained from the computational analysis can be used for virtual high-throughput screening of compound databases for yet untested inhibitors with improved properties, that may be lead compounds for  the development of novel agents and drugs.

Permeation of Solutes Across Lipid Bilayers

A second line of research in our laboratory concerns the permeation process by which small molecules or ions cross biological membranes.  The rate of permeation is of fundamental importance for many biological processes and for drug delivery.

Using liposomes as model systems for bilayer membranes , we measure the rates at which permeants cross the bilayers.   These permeability measurements are conducted using a variety of biophysical techniques, such as fluorescence and absorbance spectroscopy, stopped-flow kinetics, and the use of ion-selective electrodes.  Permeants currently under study are monovalent and divalent cations as well as some small polar compounds of biological or medicinal relevance.

Fit plot of a QSAR model showing the correlation between QSAR-computed and experimentally determined potencies (Na/K-ATPase inhibition) for a set of 43 cardiac glycosides (Stanton et al., 2007). 

The structure of the inhibitor di-tert-butylhydroquinone docked into the binding site of SERCA (Lape et al., 2007).  Docking allows the computational identification of crucial ligand/receptor interactions and visualizes the inhibitor position inside the binding pocket of an enzyme.

Structure of a liposome.  The bilayer serves a model for biological membranes.

Publications

M. Lape, C. Elam, M. Versluis, R. Kempton, and S. Paula. 2007. Molecular determinants of sarco/endoplasmic reticulum calcium ATPase inhibition by hydroquinone-based compounds. Proteins: Structure, Function, and Bioinformatics. In press..

D. Stanton, J. Ankenbauer, D. Rothgeb, M. Draper, and S. Paula. 2007. Identification and Characterization of Novel Sodium/Potassium-ATPase Inhibitors by Virtual Screening of a Compound Database. Bioorganic and Medicinal Chemistry. 15: 6062-6070.

S. Paula, N. Monson, and W. J. Ball, Jr. 2005. Structural modeling of the binding site of the human monoclonal anti-digoxin antibody 1B3. Proteins: Structure, Function, and Bioinformatics. 60: 382-391.

S. M. Keenan, R. K. Delisle, W. J. Ball, S. Paula, W. J. Welsh. 2005. A structural Model of the Digitalis Binding Site of the Na⁺,K⁺-ATPase.  Journal of Molecular Graphics and Modeling. 23: 465-475.

S. Paula, M. R. Tabet, and W. J. Ball, Jr. 2005. Interactions between cardiac glycosides and sodium/potassium-ATPase: 3D structure-activity relationship models for ligand binding to the E₂-P_i form of the enzyme versus activity inhibition.  Biochemistry. 44: 498-510.

S. Paula and W. J. Ball, Jr. 2004. The molecular determinants of thapsigargin binding to SERCA Ca²⁺-ATPase: A computational docking study.  Proteins: Structure, Function, and Bioinformatics. 56: 595-606.

 S. Paula, M. R. Tabet, A. B. Norman, and W. J. Ball, Jr. 2004. Modeling of Cocaine Binding by a Novel Human Monoclonal Antibody.  Journal of Medicinal Chemistry.  47: 133-142.

W. J. Ball, Jr., C. D. Farr, S. Paula, S. M. Keenan, R. K. DeLisle, and W. J. Welsh. 2003. Three-Dimensional Structure-Activity Relationship Modeling of Digoxin Inhibition and Docking to Na⁺,K⁺-ATPase. Annals of the New York Academy of Sciences. 986: 296-297.

S. Paula, M. R. Tabet, S. M. Keenan, W. J. Welsh, and W. J. Ball, Jr. 2002. Three-Dimensional Structure-Activity Relationship Modeling of Cocaine Binding to two Monoclonal Antibodies by Comparative Molecular Field Analysis. Journal of Molecular Biology. 325: 515-530.

J. Tittor, S. Paula, S. Subramaniam, J. Heberle, R. Henderson, D. Oesterhelt. 2002. Proton translocation by bacteriorhodopsin in the absence of substantial conformational changes. Journal of Molecular Biology.  319: 555-565.

S. Paula, J. Tittor, and D. Oesterhelt. 2001. Roles of cytoplasmic arginine and threonine in chloride transport by the bacteriorhodopsin mutant D85T. Biophysical Journal.  80: 2386-2395.

S. Paula and D. W. Deamer. 1999. Membrane permeability barriers to ionic and polar solutes. Current Topics in Membranes.  48: 77-95.

S. Paula, M. Akeson, and D. Deamer. 1999. Water transport by the bacterial channel a-hemolysin. Biochimica et Biophysica Acta. 1418: 117-126.

S. Paula, A. Sucheta, I. Szundi, and O. Einarsdóttir. 1999. Proton and electron transfer during the reduction of molecular oxygen by fully reduced cytochrome c oxidase: a flow-flash investigation using optical multichannel detection. Biochemistry. 38: 3025-3033.

S. Paula, A. G. Volkov, and D. W. Deamer. 1998. Permeation of halide anions through phospholipid bilayers occurs by the solubility-diffusion mechanism. Biophysical Journal. 74: 319-327.

A. G. Volkov, S. Paula, and D. W. Deamer. 1997. Two mechanisms of permeation of small neutral molecules and hydrated ions across phospholipid bilayers. Bioelectrochemistry and Bioenergetics. 42: 153-160.

S. Paula, A. G. Volkov, A. N. Van Hoek, T. H. Haines, and D. W. Deamer. 1996. Permeation of protons, potassium ions, and small polar molecules through phospholipid bilayers as a function of membrane thickness. Biophysical Journal. 70: 339-348.

S. Paula, W. Süss, J. Tuchtenhagen, and A. Blume. 1995. Thermodynamics of micelle formation as a function of temperature - a high sensitivity titration calorimetry study. Journal of Physical Chemistry. 99: 11742-11751.

A. Blume, J. Tuchtenhagen, and S. Paula. 1993. Application of titration calorimetry to study binding of ions, detergents, and polypeptides to lipid bilayers. Progress in Colloid and Polymer Science. 93: 118-122.

last updated:  August 29, 2007 02:29 PM