Structure and dynamics of poly(T) single-strand DNA: implications toward CPD formation

Area of Science:

• Photochemistry
• Molecular Biology
• Computational Chemistry

Background:

• UV radiation-induced cyclobutane pyrimidine dimers (thymine dimers) are critical initiators of skin cancer.
• Ultrafast studies indicate thymine dimer formation completes within 1 picosecond (ps) of UV irradiation.
• The DNA conformation at the moment of UV excitation is hypothesized to be the primary determinant of dimer formation.

Purpose of the Study:

• To investigate the populations of reactive DNA conformers in single-strand DNA (ssDNA) using molecular dynamics (MD) simulations.
• To elucidate the structural basis for thymine dimerization following UV irradiation.
• To identify potential 'hot spots' for DNA damage in ssDNA.

Main Methods:

• MD simulations were performed on an 18-thymine single-strand DNA (T18 ssDNA) over a 50 nanosecond (ns) timescale.
• Analysis of simulation trajectories focused on identifying conformations meeting the geometric criteria for thymine dimerization.
• Pairwise interaction analysis was used to predict regions of favored dimerization.

Main Results:

• Only a small fraction of T18 ssDNA conformations met the distance and dihedral angle requirements for thymine dimerization.
• This finding aligns with the experimentally observed low quantum yield of approximately 3% for dimer formation.
• Predicted 'hot spots' for DNA damage were identified based on pairwise interaction energies within the ssT18 structures.
• The role of hairpin formation via intra-strand base pairing in modulating reactivity was highlighted.

Conclusions:

• The study explains the structural origins of ultrafast thymine dimer formation observed experimentally.
• DNA conformation and hairpin formation in ssDNA are crucial factors influencing the susceptibility to UV-induced thymine dimerization.
• These findings contribute to understanding the initial events in UV-induced DNA damage and skin carcinogenesis.