Theoretical Biophysical Chemistry
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., DNA and F-actin) and exploring classical/quantum-mechanical combination methods for treating small biological molecules such as short peptides
Specific projects in the group include
A list of representative publications can be found here.
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.
Figure 1, Research - Dr. Thomasson
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.
We use MacroDox Brownian Dynamics software for our calculations. More information about Brownian Dynamics and MacroDox can be found here.
Proteins control the copying of DNA in cells. We use BD simulations of protein/DNA interactions to better understand how proteins control DNA transcription. We can predict the how the protein interacts with DNA and how long they associate. We study how these predictions are affected by changes in the composition of the solution, protein or DNA sequence. These are pioneering studies in the dynamics of protein/DNA interactions.
Figure 2, Research - Dr. Thomasson
Dynamics of an encounter of 434 Cro repressor searching the surface of DNA for its operator. The first 555 steps of a single BD trajectory beginning with the Cro center of mass (+ symbols) 60 Å away from the DNA helix axis. A few representative steps are labeled by their number in the trajectory. Note the predominant motion is towards the left indicating the Cro is sliding along the DNA.
We use MacroDox Brownian Dynamics software for our calculations. More information about Brownian Dynamics and MacroDox can be found here.
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.
Figure 3, Research - Dr. Thomasson
CD spectra predicted for cyclo(L-Pro)3. The CD predictions for structures obtained using ab initio 3-21G basis set optimizations with weighting factors created by AM1. The line curves are dipole interaction model predictions using different empirical parameter sets. The ° represent the experimental spectrum. The bandwidths are 4000 cm-1. The units for De are L mol-1 cm-1.
We use CDCalc software for our calculations. More information about Circular Dichroism and CDCalc can be found here.
"Theoretical UV Circular Dichroism of Cyclo(L-Proline-L-Proline)". Carlson, K. L.; Lowe, S. L.; Hoffmann, M. R.; Thomasson, K. A. Journal of Physical Chemistry A (2006) 110, 1925-1933.
"Identification of Specific Calcitonin-like Receptor Residues Important for Calcitonin Gene-Related Peptide High Affinity Binding". Banerjee, S.; Evanson, J.; Harris, E.; Lowe S.L.; Thomasson, K.A.; and Porter, J.E. BMC Pharmacology (2006) 6, 9.
"Theoretical UV Circular Dichroism of Aliphatic Cyclic Dipeptides". Carlson, K.L.; Lowe, S.L.; Hoffmann, M.R.; and Thomasson, K.A. . Journal of Physical Chemistry A (2005) 109, 5463-5470.
"Brownian Dynamics of Interactions Between Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) Mutants and F-actin." Waingeh, V.F.; Lowe, S.L.; Thomasson, K.A. Biopolymers (2004) 73, 533-543.
"Two Helical Conformations from a Single Foldamer Backbone: "Split Personality" in Short Alpha/Beta-Peptides." Hayden, A.; Schmitt, M.A.; Ngassa, F.N.; Thomasson, K.A.; and Gellman, S.H. Angewandte Chemie (Intl. Ed. in English) (2004) 43, 505-510.
"Brownian Dynamics of Interactions Between Aldolase Mutants and F-actin." Lowe, S.L.; Atkinson, D. M.; Waingeh, V.V.; and Thomasson, K.A. Journal of Molecular Recognition(2002) 15, 423-431.
"Dipole Interaction Model Predicted pi-pi* Circular Dichroism of Cyclo(L-Pro)3 Using Structures Created by Semi-empirical, Ab Initio, and Molecular Mechanics Methods.". S. L. Lowe, K. S. Pierce, J. Czlapinski, G. Kie-Adams, Rajeev Pandey, M. R. Hoffmann, K. A. Thomasson. Journal of Peptide Research (2003) 61, 189-201.
"Brownian Dynamics Simulations of Aldolase Binding GAPDH and the Possibility of Substrate Channeling." I. Ouporov, H. Knull, A. Huber K. Thomasson. Biophysical Journal (2001) 18, 2527-2535.
"Brownian Dynamics Simulating the Ionic Strength Dependence of the Nonspecific Association of 434 Cro Repressor Binding B-DNA." F. Yang, I. V. Ouporov, C. Fernandes, D. Motriuk, K. A. Thomasson. Journal of Physical Chemistry (2001) 105, 12601-12608.
"Brownian Dynamics Simulations of the Specific Interactions Between Rabbit Aldolase and G- or F-Actin." Ourporov, I.; Knull, H.R.; Thomasson, K.A. Biophysical Journal (1999) 76, 17-27.
Photo by Chuck Kimmerle, University Relations