Central European Journal of Chemistry Watson-Crick Base Pairs with Thiocarbonyl Groups: How Sulfur Changes the Hydrogen Bonds in DNA * E-mail: FM.Bickelhaupt@few.vu.nl Theoretische Chemie, Scheikundig Laboratorium der Vrije Universiteit, De Boelelaan 1083, NL-1081 HV Amsterdam, The Netherlands Célia Fonseca Guerra, Evert Jan Baerends, F. Matthias Bickelhaupt * Received 1 October 2007; Accepted 3 December 2007 Abstract: We have theoretically analyzed mimics of Watson-Crick AT and GC base pairs in which N–H•••O hydrogen bonds are re- placed by N–H•••S, using the generalized gradient approximation (GGA) of density functional theory at BP86/TZ2P level. The general effect of the above substitutions is an elongation and a slight weakening of the hydrogen bonds that hold together the base pairs. However, the precise effects depend on how many, and in particular, on which hydrogen bonds AT and GC are substituted.. Another purpose of this work is to clarify the relative importance of electrostatic attraction versus orbital interaction in the hydrogen bonds involved in the mimics, using a quantitative bond energy decomposition scheme. At variance with wide- spread believe, the orbital interaction component in these hydrogen bonds is found to contribute more than 40% of the attractive interactions and is thus of the same order of magnitude as the electrostatic component, which provides the remaining attraction. © Versita Warsaw and Springer-Verlag Berlin Heidelberg. Keywords: Chitosan Density functional calculations • DNA structures • Sulfur • Hydrogen bonds • Watson-Crick pair mimics Invited paper 1. Introduction Chemically modifed DNA bases, such as thioguanine, and thiouracil are of interest because of their pharmacological capabilities. [1-3] Thioguanine, which is used in the therapy of acute leukemia, is believed to exert its cytotoxic therapeutic effect by being incorporated into DNA as deoxy-6-thioguanosine. [4,5] Because of their therapeutic relevance, these modifed bases have also been the subject of theoretical studies. [6-8]. The Watson-Crick DNA base pairs have been extensively studied with ab initio theory. [9-19] In our previous work, [20-25] we showed that the generalized gradient approximation (GGA) of density functional theory (DFT) is an effcient alternative to conventional ab initio theory for accurately describing the hydrogen bonds involved in Watson-Crick base pairs (AT and GC, see Scheme 1) and in the weakly bound water dimer. [21] Our bond analyses in the frame of Kohn-Sham DFT [26] revealed that the contribution of occupied–virtual orbital interactions to the Watson-Crick hydrogen bonds is of the same order of magnitude as electrostatic interactions. [20-25] The orbital interaction component mostly originates from donor–acceptor interactions of lone pairs on nitrogen and oxygen atoms of one DNA base with empty N–H s* orbitals of the other base. [20,21,23] Very recently, we found that, at variance with widespread believe, [27-31] such an orbital interaction component is prominent even in rather weakly bound base pairs, such as those of adenine (A) with 2,4- difuorotoluene (F), a mimic of thymine (T), and of fuorine-substituted mimics of G and C, respectively. [32- 35] In these systems, the oxygen atoms are replaced by the poorer proton-acceptor fuorine and the N1–H1 of guanine is replaced by the poorer proton-donor C–H (see also Scheme 1). These fndings raise an important question: are these isolated examples, or is the occurrence of a signifcant orbital-interaction component in hydrogen bonds a more general phenomenon? In the present study, we tackle the above question by extending our analyses to a series of 6 mimics of Cent. Eur. J. Chem. • 6(1) • 2008 • 15-21 DOI: 10.2478/s11532-007-0068-y 15