Mechanism and Yields of Thymine Dimer Formation: From
Excited State Dynamics to Quantum Yields of Dimer Formation
Yu-Kay Law, Javad Azadi,
Carlos E. Crespo-Hernández, Eric D. Olmon, and
Bern Kohler
Cyclobutane pyrimidine dimers (CPDs) are the primary mutagenic photoproducts formed in significant yields when DNA is exposed to UV light. Recently, ultrafast laser spectroscopy has shown that the thymine-thymine CPD is fully formed less than 1 ps after absorption of a UV photon by the oligonucleotide (dT)18. Because motions such as helix bending and unwinding occur on longer timescales, we hypothesize that CPDs form only when adjacent pyrimidine bases are favorably aligned for reaction at the instant of photoexcitation. We used molecular dynamics (MD) simulations to explore this hypothesis by sampling conformations of thymidylyl-(3' -> 5')-thymidine (dTpdT) in water and with various organic co-solvents, and a two-parameter model was used to classify conformations into reactive and unreactive subpopulations. In support of the hypothesis that ground-state conformation controls this photoreaction, we found good agreement between the fraction of reactive conformations computed using our two-parameter model and the experimentally measured quantum yields from steady-state photochemical experiments. The set of reactive conformations that was found to have their bases parallel to each other, as determined from the MD runs, was averaged to yield a mean dimerizable structure. This structure has many characteristics in common with the structure of the cis-syn stereoisomer of the thymine dimer determined by NMR and X-ray crystallography. Analysis of the computer simulations suggest that rotation about the O5'-C5; bond is a key fluctuation that promotes conversion of an unreactive into a reactive geometry, and excited state calculations suggest that, whereas a partial bond begins to form in the mean dimerizable structure, this was not found to occur in B-form DNA. Moreover, exciton splitting was observed for the excited states of this structure - something that was not observed for the B-form geometry, but was observed in photoreversed thymine dimers in the solid state, which were found to reform thymine dimers in high yields.
Informative Motifs in Protein Family Alignments
Hatice Gulcin Ozer and William C. Ray
Consensus and sequence pattern analysis on family alignments are extensively used to identify new family members and to determine functionally and structurally important identities. Since these common approaches emphasize dominant characteristics of the family and assume residue identities are independent at each position, there is no way to describe residue preferences outside of the family consensus. In this study, we propose a novel approach to detect motifs outside the consensus of a protein family alignment via an information theoretic approach. We implemented an algorithm that discovers frequent residue motifs that are high in information content and outside of the family consensus, called informative motifs, inspired by the classic Apriori algorithm. We observed that these informative motifs are mostly spatially localized and present distinctive features of various members of the family.