Dr. Kathryn A. Thomasson
Professor and Director of Graduate StudiesB.A., 1982, University of Virginia; Ph.D., 1990, Iowa State University; Research Associate, 1990-91, Biosym Technologies, Inc.; Dreyfus Postdoctoral Fellow, 1992-93, Tennessee Technological University.
Research in my laboratory incorporates large-scale computer simulations with classical physics, chemistry and biology. Current developments include expanding programs to treat large biological molecules (e.g., proteins and DNA) and exploring quantum mechanical methods for treating small biological molecules such as short peptides. Specific projects in the group include: (1) channeling within molecules of the glycolytic pathwaty, (2) glycolytic enzyme interactions with cytoskeletal structures, and (3) calculating the circular dichroic spectra of peptides and proteins. Examples of each follow.
(1) Functional protein-protein interactions are essential for many physiological processes and may play important roles in substrate channeling, coenzyme transfer, and compartmentation in glycolysis. Brownian dynamics (BD) elucidates the interactions between the glycolytic enzymes glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and lactate dehydrogenase (LDH) and the transfer of the cofactor nicotinamide adenine dinucleotide (NAD) between LDH and GAPDH. BD demonstrates that GAPDH and LDH form complexes of four different binding modes that are stabilized by salt bridges. The efficiency of NAD transfer, determined by the relative number of BD trajectories that reached any active site of LDH or GAPDH, is higher when the cofactor NAD is transferred within a GAPDH/LDH complex by approximately a factor of six compared to transfer from solution. The average transfer time of NAD from solution to the free enzymes is 500 ns compared to 56-360 ns when NAD is transferred between active sites of a GAPDH/LDH complex. Similarly, the frequency distribution profiles of transfer times suggest a preference for channeling NAD between GAPDH and LDH as compared to diffusing from solution. Channeling transfer seems more efficient than solution transfer due to active site proximity, favorable electrostatics, and complex geometry.
Channeling Profile Showing the Pathway of NAD Transfer between GAPDH and LDH. The enzymes are rendered as ribbons (blue, GAPDH; green, LDH). NAD is rendered as red spheres. The NAD starting position is on GAPDH and ending point is on LDH.
(2) The cytoskeletal structure, F-actin creates a structure in the cell cytoplasm upon which glycolytic enzymes associate and dissociate dynamically, and these dynamic associations are important to organizing the reactions in the glycolytic pathway. Many glycolytic enzymes including fructose-1,6-bisphophsate aldolase (aldolase), glycerladehyde-3-phosphate dehydrogenase (GAPDH), and lactate dehydrogenase (LDH) bind actin reversibly. Other enzymes such as triose phosphate isomerase (TIM) bind indirectly through interactions with the enzymes that bind. We use and enhance existing theoretical methods to better investigate the interactions of F-actin with glycolytic enzymes. The method of Brownian dynamics (BD) predicts the various kinds of complexes between F-actin and the glycolytic enzymes, provides the relative stability of complexes, reproduces experimentally observed factors on binding such as ionic strength, pH, and relative binding affinities, and make predictions about the impact of mutations on the proteins.
Complex of aldolase (blue) with a subunit of the cytoskeletal structure F-actin (red). Two subunits of aldolase bind a single subunit of F-actin by forming salt brigdes from lysines on the surface of aldolase to aspartates and glutamates in subdomain 1 of F-actin.
(3) One of the most serious unsolved problems in computational biology today is the lack of ability to predict the three-dimensional structure of a protein from its primary sequence. The lack of progress in this area is now the scientific bottleneck for understanding proteins and their function, particularly concerning the solution of the human and other genomes and high throughput proteomics. It is critical to provide a computationally fast effective method to predict the structure of a protein as its primary sequence is discovered. One quick way to experimentally determine a solution structure is the circular dichroism (CD) spectrum. We use classical electromagnetic theory (the dipole interaction model) to predict CD for peptides and proteins that can provide an excellent test of proposed protein models when the CD predictions agree with experiment. In collaboration with Dr. Mark Hoffmann, we are developing a classical/quantum mechanical approach to generating the peptide models used to predict CD.
Lysozyme Structure and Cicrular Dichroism. Left Panel: secondary structural element profile: red cylinders are α-helices; blue arrows are turn structures, yellow ribbons are β-sheets, and green ribbons are other. Right Panel: corresponding Synchrotron Radiation Circular Dichroism spectrum as found in the Protein Circular Dichroism Data Base (blue) and DInaMo calculated CD spectrum (red).
Elizabeth Spanbauer Schmidt, Neville Y. Forlemu, Eric N. Njabon, Kathryn A. Thomasson. BD Simulations of the Ionic Strength Dependence of the Interactions Between Triose Phosphate Isomerase and F-Actin. Journal of Undergraduate Chemistry Research, 9(4) (2010) 87-96. Scheme 1 was featured on the cover of the journal.
E. M. Nkabyo, E. A. Lindsey, B. E. Haines, K. A. Thomasson, and F. N. Ngassa. Understanding The Interactions of β-Peptides with Each Other and with the Fos and Jun Units of the Human Leucine Zipper: A Computational Modeling Study. Journal of Undergraduate Chemistry Research, 7(3) (2008) 98-107.
Mahesh K. Lakshman, John C. Keeler, Felix N. Ngassa, John H. Hilmer, Padmanava Pradhan, Barbara Zajc, Kathryn A. Thomasson. "Highly Diastereoselective Synthesis of Nucleoside Adducts From the Carcinogenic Benzo[A]Pyrene Diol Epoxide and a Computational Analysis." J. Amer. Chem. Soc. 129 (2007) 68-76.
Neville Y. Forlemu, Victor F. Waingeh, Igor V. Ouporov, Stephen L. Lowe, Kathryn A. Thomasson. Theoretical Study of Interactions between Aldolase and F-actin: Insight into Different Species. Biopolymers, 85 (2007) 60-71, PMID:1703493. Figure 3 of this paper was featured on the cover of the journal.
V. F. Waingeh, C.D. Gustafson, E. I. Kozliak, S. L. Lowe, H. R. Knull, K. A. Thomasson. "Glycolytic Enzyme Interactions with Yeast and Skeletal Muscle F-actin." Biophys. J. 90 (2006) 1371-1384, PMID: 16326908.
K. L. Carlson, M. R. Hoffmann, K. A. Thomasson. "Geometric Optimization of Cyclo(L-Proline-L-Proline) and Prediction of its UV Circular Dichroic Spectrum." J. Phys. Chem. A 110 (2006) 1925-1933.
Sugato Banerjee, Janel Evanson, Erik Harris, Stephen L. Lowe, Kathryn A. Thomasson, James E. Porter. Identification of Specific Calcitonin-like Receptor Residues Important for Calcitonin Gene-Related Peptide High Affinity Binding. BMC Pharmacology, 6:9 (2006) available online at http://www.biomedcentral.com/1471-2210/6/9.
K. L. Carlson, S. L. Lowe, M. R. Hoffmann, K. A. Thomasson. "Theoretical UV Circular Dichroism of Aliphatic Cyclic Dipeptides." J. Phys. Chem. A, 109 (2005) 5463-5470.
V. Waingeh, S. Lowe, K. Thomasson. Brownian Dynamics of Interactions between Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) Mutants and F-actin. Biopolymers, 73, 533-541 (2004) PMID: 15048777.
A. Hayen, M. A. Schmitt, F. Ngassa, K. A. Thomasson, S. H. Gellman. Foldamers with Heterogeneous Backbones: Two Helical Conformations from a Single Foldamer Backbone: Split Personality in Short α/β-Peptides. Angewandte Chemie, 43, 505-510 (2004).
A. Huber, E. Nkabyo, R. Warnok, A. Skalsky, M. Kuzel, V. J. Gelling, T. B. Dillman, M. Ward, R. Guo, G. Kie-Adams, S. Vollmer, F. N. Ngassa, S. L. Lowe, I. V. Ouporov, K. A. Thomasson. "A Conformational Search and Calculation of the Circular Dichroic Spectrum of the Flexible Peptide Cylco(Gly-Pro-Gly)2 Using the Dipole Interaction Model". J. Undergrad. Chem. Res., 4, 145-161 (2003).
S. Lowe, C. Adrian, I. Ouporov, V. Waingeh, K. Thomasson. "Brownian Dynamics Simulations of Glycolytic Enzyme Subsets with F-actin." Biopolymers, 70, 456-470 (2003) PMID: 14648757.
S. L. Lowe, K. S. Pierce, J. Czlapinski, G. Kie-Adams, Rajeev Pandey, M. R. Hoffmann, K. A. Thomasson. "Dipole Interaction Model Predicted ∏-∏* Circular Dichroism of Cyclo(L-Pro)3 Using Structures Created by Semi-empirical, Ab Initio, and Molecular Mechanics Methods." J. Peptide Research, 61, 189-201 (2003).
S. L. Lowe, D. M. Atkinson, V. Waingeh, K. A. Thomasson. "Brownian Dynamics of Interactions Between Aldolase Mutants and F-Actin." J. Mol. Recognition, 15, 423-431 (2002) PMID: 12501161.
F. Yang, I. V. Ouporov, C. Fernandes, D. Motriuk, K. A. Thomasson. "Brownian Dynamics Simulating the Ionic Strength Dependence of the Nonspecific Association of 434 Cro Repressor Binding B-DNA." J. Phys. Chem. 105,12601-12608 (2001).
I. Ouporov, H. Knull, A. Huber K. Thomasson. "Brownian Dynamics Simulations of Aldolase Binding GAPDH and the Possibility of Substrate Channeling." Biophysical Journal, 18, 2527-2535 (2001) PMID: 11371431. This article was cited (9/02) by the Rebecca Wade in the Faculty of Thousand as recommended reading for structural biology:
I. Ouporov, H. Knull, S. L. Lowe, K. Thomasson. "Interactions of Glyceraldehyde-3-phosphate Dehydrogenase with G- and F-actin Predicted by Brownian Dynamics." J. Molecular Recognition, 14 (2001) 29-41, PMID: 11180560.
I. Ouporov, T. Kieth, H. Knull, K. Thomasson. "Computer Simulations of Glycolytic Enzyme Interactions with F-actin." J. Biomolecular Structure and Dynamics 18 (2000) 311-323, PMID: 11089651.
I. Ourporov, H. R. Knull, K. A. Thomasson. "Brownian Dynamics Simulations of the Specific Interactions Between Rabbit Aldolase and G- or F-Actin." Biophys. J., 76 (1999) 17-27, PMID: 9876119. This article was quoted in Current Awareness in Biomedicine, Cytoskeleton, March 1999.
S. Sun, J. Saltmarsh, S. Mallik, K. Thomasson. "Molecular Recognition of a Tris(Histidine) Ligand." Chemical Communication, 4 (1998) 519-520.
K. A. Thomasson, S. Merschman, M. Humbert, N. Kulevsky. "Applying Statistics in the Undergraduate Chemistry Laboratory: Experiments with Food Dyes." Journal of Chemical Education, 75 (1998) 231-233.
K. A. Thomasson, I. V. Ouporov, T. Baumgartner, J. Czlapinski, T. Kaldor, S. H. Northrup. "Free Energy of Nonspecific Binding of Cro Repressor Protein to DNA." Journal of Physical Chemistry B, 101 (1997) 9127-9136.
K. J. MacFarlane, M. M. Humbert, K. A. Thomasson. "Force Field Dependence of Boltzmann Weighting Factors on Predicted ∏-∏* Circular Dichroic Spectra of Cyclo(Gly-Pro-Gly)2." International Journal of Peptide Protein Research, 47 (1996) 447-459.
D. A. Fitzwater, K. A. Thomasson, R. J. Glinski. "A Modular Raman Spectroscopy System Using a Helium-Neon Laser That Is Also Suited For Emission Spectrophotometry Experiments." Journal of Chemical Education, 72 (1995) 187-189.
S. M. Andrew, K. A. Thomasson, S. H. Northrup. "Simulation of Electron Transfer Self-Exchange Kinetics of Cytochromes c and b5", Journal of the American Chemical Society, 115, (1993) 5516-5521.
S. H. Northrup, K. A. Thomasson, C. M. Miller, L. D. Eltis, P. D. Barker, A. G. Mauk. "Effects of Charged Amino Acid Mutations on the Bimolecular Kinetics of Reduction of Yeast iso-1-ferricytochrome c by Bovine ferrocytochrome b5", Biochemistry, 32, (1993) 6613-6623, PMID: 8392365.
K. A. Thomasson, J. B. Applequist. "Effects of Proline Ring Conformation on Theoretical ∏-∏* Absorption and Circular Dichroic Spectra of Helical Poly(L-proline) Forms I and II". Biopolymers, 31 (1991) 529-535.
K. A. Thomasson, J. B. Applequist. "Bond Optimized Ring Closure for Proline: Comparison of Conformations and Semiempirical Energies with Small Molecule X-ray Structure". Biopolymers, 30 (1990) 437-450.