Poster abstracts

Poster number 44 submitted by Yu Kay Law

Cyclobutane Pyrimidine Dimer Formation in Oligonucleotides: Effects of Base Stacking and Base Pairing

Yu Kay Law (Biophysics Program, The Ohio State University, Columbus), Marc P. Coons (Department of Chemistry, The Ohio State University, Columbus), Javad Azadi (Department of Chemistry, The Ohio State University, Columbus), Bern Kohler (Department of Chemistry and Biophysics Program, The Ohio State University, Columbus)

Abstract:
Cyclobutane pyrimidine dimers (CPDs) are the most commonly formed mutagenic photolesion upon UV irradiation of DNA. Although experiments have suggested strong structural dependence on dimer formation, until recently no model exists which can predict structures that form CPDs upon photoexcitation. Recent time-resolved experiments (1) have suggested that this can be predicted from the ground state geometry at the time of excitation. This allows for models developed using classical molecular dynamics simulations, as the application of this insight does not require the determination of excited state energy surfaces, but rather large-scale sampling of atomic-scale molecular geometries. Using our two-parameter model (2), we have been able to predict the quantum yields of dimerization within the limits of experimental error for dTpdT in various co-solvent environments, as well as predict the quantum yield of dimerization in poly(dT) within a factor of two. However, this model underestimates dimer yields in the analogous poly(dA)•poly(dT) system. Using quantum mechanical calculations to explore the importance of various structural parameters and suggest other photochemical models for this photoreaction, we will explore whether this is a function of the inherent bias of simulations of double-stranded DNA to B-form DNA or if this indicates deficiencies in our earlier two-parameter model through comparison of the quantum yields predicted using different models with experimental values. We also suggest that in such oligomer systems dimer formation entails rotation mostly about the glycosidic torsional bonds and, to a lesser extent, to a change in sugar puckering, as opposed to backbone rotation as was suggested for dTpdT.

References:
(1) Schreier, W. J.; Schrader, T. E.; Koller, F. O.; Gilch, P.; Crespo-Hernández, C. E.; Swaminathan, V. N.; Carell, T.; Zinth, W.; Kohler, B. Science 2007, 315, 625-629.
(2) Law, Y. K.; Azadi, J.; Crespo-Hernández, C. E.; Olmon, E.; Kohler, B. Biophys. J. 2008, 94, 3590-3600.

Keywords: molecular dynamics, thymine dimer, DNA