TAUTOMERIZATION IN BIOMOLECULES as Investigated by Quantum Chemistry and Molecular Dynamics:

1. Ninth Triennial Congress of the WORLD ASSOCIATION OF THEORETICAL AND COMPUTATIONAL CHEMISTS Santiago de Compostela (Spain), 17-22 July, 2011. TAUTOMERIZATION IN BIOMOLECULES as Investigated by Quantum Chemistry and Molecular Dynamics: Cytosine and Cytidine Géza Fogarasi, Institute of Chemistry, Eötvös Loránd University, Budapest, H-1518, Pf. 32. Dynamics Study Method: ab initio Born-Oppenheimer dynamics Motivation Intramolecular proton transfer (tautomerism) is a ubiquitous phenomenon both in chemistry and biology. In DNA, tautomerization of the nucleotide bases is one of the possible mechanisms of mutation [1].. Philosophy: The notion of reaction mechanisms is based on the Born-Oppenheimer (B-O) approximation: atoms move on a potential energy surface (PES) defined by the electronic energy as a function of nuclear positions. In the simplest models reactions follow the minimum energy pathway (MEP), going through a transition state (TS). The MEP expressed in mass-weighted Cartesians is referred to as the internal reaction coordinate, IRC. However: computations have shown that reactions may follow a route totally different from the IRC [4,5]. True dynamics calculations require knowledge of the complete PES, and recent methods generate it "on the fly". In contrast to "propagation" of the Car-Parrinello method, in B-O dynamics the wave function is fully optimized in each step along the trajectory. Energy and first derivatives are determined from an ab initio wf, and atomic movements calculated from them classically. Introduction Crystalline cytosine contains only the keto form, while a mixture of various isomers may exist in the vapor state, suggested both by spectroscopy and by quantum chemistry (QC), see Scheme 1. The intriguing question is the mechanism: how do tautomers form under given experimental circumstances? Procedure [3] 1. Start geometry not too far from equilibrium 2. The atomic nuclei get a random kicksuch that the average kinetic energy corresponds to a selected temperature. 3. Energy and FORCES calculated from ab initio Quantum Chemistry ‘on the fly’ 4. Movement of atoms calculated classically 5. GOTO 3 Scheme 1. Three tautomers of cytosine, with two rotamers indicated. Isolated bases have prohibitively high transition state (TS) energies of 40-50 kcal/mol, shown by numerous QC calculations. However, traces of water may play a crucial role as water reduces the barrier by about a half [2].In addition, the interesting possibility of bimolecular tautomerization through H-bonded dimers has been suggested [3,4]. The focus of the present study will be on this latter question. Concerted and synchronous reaction: Figure 1. Three H-bonded dimers derived from 1. : E(TS) = 6.3 kcal/mol : E(TS) = 4.90 kcal/mol : E(TS) = 7.7 kcal/mol Table 1. QC-calculated energies for cytosine dimers and transition states dimer dimer Computational details The basis set was aug-cc-pVDZ. level using the PQS package [12]. Concerted but not synchronous reaction: 1Energy of the H-bonded dimer. 2Transition state barrier relative to the H-bonded dimer, (TS) (Min). Ee and Eo w/o and with ZPE, resp. 3Energy of the dimer relative to two isolated monomers of the keto form, i.e. the stabilization energy due to H-bonds, w/o and with ZPE. _____________________________________________________________________ [1] J.D. Watson and F.H.C. Crick, Nature 171, 964-967 (1953). [2] G. Fogarasi, J. Phys. Chem. A 106, 1381-1390 (2002). [3] a) L. Sun, K. Song, W.L. Hase, Science296, 875-878 (2002). b) S. C. Ammal, H. Yamataka, M.Aida, M. Dupuis, Science 299, 1555-1557.(2003). [4] P. Pulay, G. Fogarasi, Chem. Phys. Lett., 386, 272-278 (2004). [4] M. Szczesniak, K. Szczepaniak, J.S. Kwiatkowski, K. Kubulat and W.B. Person, J. Am. Chem. Soc. 110, 8319-8330 (1988). [5] M.J. Nowak, L. Lapinski, J. Fulara, Spectrochim. Acta A, 45A, 229 (1989). [ [7] G. Fogarasi, Chem. Phys., 349, 204-209 (2008). [8] Z. Yang and M. T. Rodgers, Phys. Chem. Chem. Phys. 6, 2749-2757 (2004). [9] O. Kostko, K. Bravaya, A. Krylov, M. Ahmed, Phys. Chem. Chem. Phys. 12, 2860 – 2872 (2010). [10] CFOUR, a quantum chemical program package written by J. F. Stanton, J. Gauss, M. E. Harding, P. G. Szalay. [11] H. Köppel, W. Domcke, L. S. Cederbaum, Adv. Chem. Phys.1984, 57, 59-246. [12] PQS version 2.3, Parallel Quantum Solutions, 2013 Green Acres Road, Fayetteville, Arkansas 72703. t/fs 100 110 120 130 140 Acknowledgement.Financial support by the Hungarian Scientific Research Foundation (OTKA, Grant No. T68427) is gratefully acknowledged. The European Union and the European Social Fund have provided financial support to the project under the grant no. TAMOP 4.2.1./B-09/KMR-2010-0003. t/fs 150 160 170 180 190 Figure 2 Tautomerization from H-bonded dimer 1:1 to 3a:2b