Ab Initio Kinetic Simulation of Gas-Phase Experiments: Tautomerization of Cytosine and Guanine Dmytro Kosenkov, † Yana Kholod, † Leonid Gorb, †,‡ Oleg Shishkin, § Dmytro M. Hovorun, ‡ Michel Mons, | and Jerzy Leszczynski* ,† Interdisciplinary Center for Nanotoxicity, Department of Chemistry, Jackson State UniVersity, Jackson, Mississippi 39217, Department of Molecular and Quantum Biophysics, Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, 150 Zabolotnoho Vul., KyiV 03143, Ukraine, STC “Institute for Single Crystals”, National Academy of Sciences of Ukraine, KharkiV 61001, Ukraine, and Laboratoire Francis Perrin (URA CEA CNRS 2453), IRAMIS/SerVice des Photons, Atomes et Mole ´cules, CEA Saclay, Ba ˆt. 522, 91191 Gif-sur-YVette Cedex, France ReceiVed: December 2, 2008; ReVised Manuscript ReceiVed: February 9, 2009 A novel kinetic approach based on ab initio calculated rate constants has been developed and implemented in the kTSim program. The proposed approach allows prediction of the distribution of reactant and product concentrations over time, based exclusively on computationally obtained rate constants. The newly developed methodology was used to simulate the process of evaporation and tautomerization of guanine and cytosine under thermal (T ) 490 K, cytosine; T ) 620 K, guanine) and laser (T ) 1000 K, 24 ns laser pulse) desorption conditions. Both monomolecular and bimolecular mechanisms of the tautomerization were considered simultaneously. The rates of the reactions were estimated using the values of Gibbs free energies calculated at the MPWB1K/aug-cc-pVDZ level and specified in a kTSim input. We expect that the proposed approach can also be used for accurate kinetic simulation of a wide range of processes. I. Introduction Nucleic acid bases cytosine and guanine represent DNA and RNA building blocks. These nucleobases together with adenine, thymine, and uracil are responsible for storage and transduction of genetic information. 1,2 Being incorporated into DNA, the nucleobases exist in one predominant keto form: CK for cytosine (Figure 1) and G9K for guanine (Figure 2). However, other “rare” tautomeric enol and imino forms are also known (Figures 1 and 2). These rare tautomers of the nucleobases have been suggested as a possible reason for spontaneous point mutations in DNA. 2-4 A recent investigation of the human genome has also revealed a number of single-nucleotide substitutions (point mutations) in the genome. This phenomenon is called “a single- nucleotide polymorphism” (SNP). 5 These substitutions are viewed as very sensitive biological markers for prediction of a specific individual response to certain drugs, susceptibility to environmental factors, and risk of disease development. 5,6 Numerous computational data confirm an ability of cytosine and guanine to form rare tautomers in the gas phase. 4,9,10,17-26 Recently, remarkable progress in the understanding of photo- excitation and deactivation pathways of excited nucleobases has been achieved. 27-30 Tautomers of nucleic acid bases could cause spontaneous point mutations with rates of 10 -8 -10 -10 (in vivo) and 10 -6 -10 -5 (in vitro). 7,8 In other words, their concentrations are extremely small and can hardly be detected even with modern experimental techniques. In addition, due to small concentrations the enol and imino tautomers have not been observed in the condensed phase. However, experiments performed in the gas phase indicate the presence of rare tautomers. Therefore, experimental techniques such as matrix isolation, 9 the He nanodroplet method, 10,11 and resonance-enhanced multiphoton ionization (REMPI) spectroscopy 12-16 are the main sources of experimental information on the physical and chemical proper- ties of canonic and rare tautomers. However, each of the techniques requires very different conditions. In the matrix isolation and He nanodroplet experiments thermal desorption is used for sample evaporation, while in the REMPI experiments laser desorption is employed. Thus, the experimental results sometimes differ in the structure and concentration of the observed tautomers. Further- more, REMPI spectroscopy is limited in its ability to measure the concentrations of the observed tautomers. To overcome these restrictions of the experimental techniques, here we have modeled evaporation of a solid sample of selected DNA bases and estimated the relative populations of the tautomers. Ab initio methods were employed to predict the * To whom correspondence should be addressed. Phone: (601) 979-3723. Fax: (601) 979-7823. E-mail: jerzy@ccmsi.us. † Jackson State University. ‡ Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine. § STC “Institute for Single Crystals”, National Academy of Sciences of Ukraine. | CEA Saclay. Figure 1. Cytosine canonic keto (CK) and rare enol (CE) and imino (CI) tautomers. J. Phys. Chem. B 2009, 113, 6140–6150 6140 10.1021/jp810570w CCC: $40.75  2009 American Chemical Society Published on Web 04/07/2009