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.
Bibliographical noteFunding Information:
This work was supported by the Ministerio de Ciencia, Innovación y Universidades of Spain (Projects PGC2018-094644-B-C21 and PID2019-106732GB-I00). E.V. and I.C. gratefully acknowledge the “Ramón y Cajal” program and a Formación de Profesorado Universitario contract of the Ministerio de Economı́a y Competitividad of Spain. This work was also supported by the Air Force Office of Scientific Research by Grant FA9550-16-1-0134. T.S. acknowledges that this material is also based upon work supported by the National Science Foundation Graduate Research Fellowship Program under Grant CON-75851 and Project 00074041. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation. The authors acknowledge the Minnesota Supercomputing Institute (MSI) at the University of Minnesota and the Red Española de Supercomputación, the CESGA Supercomputer Center (Finisterrae), the Centro de Computación Cientı́fica of the UAM (CCC-UAM) for providing resources that contributed to the research results reported within this paper and for their continued technical support.