Robert B. Macgregor, Jr.
Professor, Ph.D. (Illinois-Urbana)

KINETICS AND THERMODYNAMICS OF NON-COVALENT INTERACTIONS. NOVEL DNA STRUCTURES

Protein folding, gene regulation, drug interactions, and membrane formation depend on the ability of structurally correct com-plexes forming at the right time and place within a cell. The research in my lab-or-atory is directed toward understanding the role of non-covalent interactions in determining the structural stability of macro-mo-lecular complexes, especially those involving complexes with DNA. The results of this research are important to the under-standing of the physical basis for biological regulation, the origin of some diseases, and for the development of new drugs. The research is multi-disciplinary, involving techniques and principles of biochemistry, kinetics, mol-ec-ular biology, physical chemistry and spectroscopy.

There are three lines of research in the laboratory:

1. The physical chemistry of complexes formed with DNA. The formation of a DNA-protein complex is the result of many non-covalent contacts; these may involve electrostatic, hydrogen bonding, or hydrophobic interactions. An individual contact may enhance or dim-in-ish the overall stability of the complex. Under-standing the relative importance of the contacts to the formation of the DNA-protein complex is of fundamental importance to elucidating the molecular mechanisms of genetic regulation. This know-ledge would also be useful in design-ing new drugs that can interact with DNA in a desired manner. We are investigating the complex DNA forms with proteins, peptides and small drugs using several experimental approaches.
   
   
2. Formation and Structural Determinants of Non-canonical DNA Structures. The ability to ther-a-peut-ic-ally control genetic expression by introducing synthetic oligonucleotides into cells is called antisense or antigene ther-apy. The fundamental interactions in these novel therapies involve unusual DNA struc-tures such as three- and four-stranded DNA structures. An example of an unusual DNA assembly is our recent discovery of multi stranded DNA species that we have called frayed wires. To fully realize the potential of the new methods, we are study-ing the chemical, physical and biological characteristics of a variety of non-standard DNA structures.
   
   
3. Novel Sterilization Technologies. Sterilization is an important step in the manufacture of dosage forms and medical devices. However, the extreme requirements needed to assure elimination of all micro-organisms is often incompatible with the sensitivity of pharmaceuticals and medical devices to the sterilization conditions. We are developing new methods of sterilization based upon the use of elevated hydrostatic pressure.

A Thermodynamic basis of DNA sequence selectivity by the ETS domain of murine PU.1.
G. M. K. Poon & R. B. Macgregor, Jr. (2004) J Mol Biol, 335, 113 - 27.

Volumetric properties of the formation of double stranded DNA: A nearest-neighbour analysis.
D. N. Dubins & R. B. Macgregor, Jr. (2004) Biopolymers, 73, 242 – 257.

Ionic mobilities of duplex and frayed wire DNA in discontinuous buffer electrophoresis: evidence of interactions with amino acids
G. M. K. Poon, R. M. Abu-Ghazalah, & R. B. Macgregor, Jr. (2004) Biochemistry, 43, 16337 – 16347.

Comparison of the Heat– and Pressure-Induced Helix-Coil Transition of Two DNA Copolymers
G. Rayan & R. B. Macgregor, Jr. (2005) J. Phys. Chem. B, 109, 15558 – 15565. 

Temperature Dependence of the Volumetric Parameters of Drug Binding to Poly[d(A-T)]•poly[d(A-T)] and Poly(dA)•poly(dT)
X. Shi & R. B. Macgregor, Jr. (2006) Biophysical Journal, 90, 1729 – 1738.

In Vivo Disposition and Stability of DNA Frayed Wires in Mice
M. F. Yanze, E. A. Ho, R. B. Macgregor, Jr., & M. Piquette-Miller (2006) Int. J. Biol. Macromol., 39, 310 - 316.

Volume and Hydration Changes of DNA Ligand Interactions
X. Shi & R. B. Macgregor, Jr. (2007) Biophysical Chemistry, 125, 471 - 482.

The Effect of Charge on the Volume Change of DNA Binding with Intercalator DAPP
X. Shi & R. B. Macgregor, Jr. (2007) J. Phys. Chem. B, 111, 3321 – 3324.

Effect of Cesium on the Volume of the Helix-coil Transition of DNA and DNA-Ligand Complex Formation
X. Shi & R. B. Macgregor, Jr. (2007) Biophysical Chemistry, 130, 93 – 101.

Link to publications in PubMed

Mailing Address:
Leslie Dan Faculty of Pharmacy, University of Toronto
144 College Street
Toronto, Ontario Canada M5S 3M2

Tel: (416) 978-7332
Fax: (416) 978-8511

E-mail: rob.macgregor@utoronto.ca

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