A theoretical investigation of tautomeric equilibria and proton transfer in isolated and hydrated thiocytosine Yevgeniy Podolyan, Leonid Gorb, Alvin Blue, Jerzy Leszczynski * Department of Chemistry, Computational Center for Molecular Structure and Interactions, Jackson State University, 1400 J.R. Lynch Street, P.O. Box 17910, Jackson, MS 39217-0510, USA Received 30 November 2000; revised 14 February 2001; accepted 15 February 2001 Abstract The results of an ab initio post Hartree±Fock study of the relative stabilities and mechanism of intramolecular proton transfer in isolated and monohydrated thiocytosine are reported. The geometries of local minima and transition states were optimized without symmetry restrictions by the gradient procedure at the HF and MP2 levels of theory and were veri®ed by energy second derivative calculations. The standard 6-31Gd) basis set was used. The single point calculations have been performed at the MP4SDQ)/6-31 1 Gd,p)//MP2/6-31Gd) and MP2/6-31111Gd,p)//MP2/6-31Gd) approximations. The post Hartree±Fock ab initio theory predicts different distributions of the tautomers for cytosine and thiocytosine both in the gas phase and in polar media PCM solvation model). Interaction of thiocytosine tautomers with one water molecule decreases the difference in the energies of the two most stable tautomers signi®cantly but does not change the order of the stability of tautomers. However, ®ve water molecules forming a ®rst solvation shell change the stability pattern. The heights of the barriers of sulfur-involved proton transfers in thiocytosine are much smaller than analogous barriers in cytosine. In contrast, corresponding barriers for the complexes with one water molecule are higher in thiocytosine. q 2001 Elsevier Science B.V. All rights reserved. Keywords: Cytosine; Thiocytosine; Proton transfer; Local hydration; Tautomeric equilibria 1. Introduction 2-Thiocytosine TC) is an analog of the natural nucleic acid base cytosine whose oxygen atom is substituted by sulfur atom Scheme 1). Even though thiocytosine was found neither in natural mammal's DNA nor RNA nucleic acids, it was detected in tRNA molecules in Escherichia coli [1±3]. Its nucleosides exhibit moderate inhibitory activity against vaccine and Epstein±Barr viruses in cell cultures [4,5], and ¯uorinated 2-thiocytosine has recently shown poten- tial antileukemic activity [6]. Tautomerism of cytosine was studied very exten- sively both experimentally and theoretically. It was shown that in the gas phase cytosine exists primarily in forms of two stable tautomers, hydroxo-amino and carboxo-amino-forms.Thereisalsosomeevidencefor the presence of a small amount of the carboxo-imino- form. Theoretical investigations of the tautomeric stabilities of different cytosine forms are in agreement with the experimental results. Recently, we also performed theoretical study of the proton transfer in isolated and monohydrated cytosine tautomers [7]. Tautomerism of thiocytosine has not been studied as frequently as that of cytosine. There are several Journal of Molecular Structure Theochem) 549 2001) 101±109 0166-1280/01/$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. PII: S0166-128001)00483-3 www.elsevier.com/locate/theochem * Corresponding author. Tel.: 11-601-979-3723; fax: 11-601- 979-7823. E-mail address: jerzy@ccmsi.jsums.edu J. Leszczynski).