TY - JOUR
T1 - Intrastrand photolesion formation in thio-substituted DNA
T2 - A case study including single-reference and multireference methods
AU - Vos, Eva
AU - Scott, Thais R.
AU - González-Vázquez, Jesús
AU - Corral, Inés
AU - Truhlar, Donald G.
AU - Gagliardi, Laura
N1 - Publisher Copyright:
© 2020 American Chemical Society
PY - 2020/12/17
Y1 - 2020/12/17
N2 - The substitution of canonical nucleobases by thiated analogues in natural DNA has been exploited in pharmacology, photochemotherapy, and structural biology. Thionucleobases react with adjacent thymines leading to 6-4 pyrimidine−pyrimidone photoproducts (6-4PPs), which are a major source of DNA photodamage, in particular intrastrand cross-linked photolesions. Here, we study the mechanism responsible for the formation of 6-4PPs in thionucleobases by employing quantum-mechanical calculations. We use multiconfiguration pair-density functional theory, complete active space second-order perturbation theory, and Kohn−Sham density functional theory. Scrutinizing the photochemistry of thionucleobases can elucidate the reaction mechanism of these prodrugs and identify the role that triplet excited states play in the generation of photolesions in the natural biopolymer. Three different possible mechanisms to generate the 6-4PPs are presented, and we conclude that the use of multireference approaches is indispensable to capture important features of the potential energy surface.
AB - The substitution of canonical nucleobases by thiated analogues in natural DNA has been exploited in pharmacology, photochemotherapy, and structural biology. Thionucleobases react with adjacent thymines leading to 6-4 pyrimidine−pyrimidone photoproducts (6-4PPs), which are a major source of DNA photodamage, in particular intrastrand cross-linked photolesions. Here, we study the mechanism responsible for the formation of 6-4PPs in thionucleobases by employing quantum-mechanical calculations. We use multiconfiguration pair-density functional theory, complete active space second-order perturbation theory, and Kohn−Sham density functional theory. Scrutinizing the photochemistry of thionucleobases can elucidate the reaction mechanism of these prodrugs and identify the role that triplet excited states play in the generation of photolesions in the natural biopolymer. Three different possible mechanisms to generate the 6-4PPs are presented, and we conclude that the use of multireference approaches is indispensable to capture important features of the potential energy surface.
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U2 - 10.1021/acs.jpca.0c06814
DO - 10.1021/acs.jpca.0c06814
M3 - Article
C2 - 33284609
AN - SCOPUS:85097750156
SN - 1089-5639
VL - 124
SP - 10422
EP - 10433
JO - Journal of Physical Chemistry A
JF - Journal of Physical Chemistry A
IS - 50
ER -