Ground-State Properties of Nucleic Acid Constituents Studied by Density Functional Calculations. 3. Role of Sugar Puckering and Base Orientation on the Energetics and Geometry of 2′-Deoxyribonucleosides and Ribonucleosides Alexandre Hocquet, Nicolas Leulliot, and Mahmoud Ghomi* Laboratoire de Physicochimie Biomole ´ culaire et Cellulaire, UPRESA CNRS 7033, Case courrier 138, UniVersite ´ Pierre et Marie Curie, 4 Place Jussieu, F-75252 Paris Cedex 05, France ReceiVed: NoVember 17, 1999; In Final Form: February 18, 2000 In the present paper, we have analyzed the conformational energy and geometrical parameters of the isolated 2′-deoxyribonucleosides and ribonucleosides. Geometry optimization of these nucleic acid constituents has been undertaken by means of density functional theory with the Becke-Lee-Yang-Parr exchange and correlation functional and split valence basis sets, 6-31G (/) , including nonstandard polarization functions on carbon, nitrogen, and oxygen atoms. For each nucleoside, three major conformers, i.e., C2′-endo/anti, C3′- endo/anti, and C3′-endo/syn, have been taken into consideration, where C3′-endo and C2′-endo refer to the north (N)-type and south (S)-type sugar puckering, respectively, and anti and syn designate the orientation of the base with respect to the sugar. In both families (2′-deoxyribonucleosides and ribonucleosides) the anti orientation of the base stabilized by an intramolecular C-H‚‚‚O hydrogen bond formed between the base and the O5′ atom of the sugar moiety corresponds to the lowest energy states. In the 2′-deoxyribonucleosides including uracil, guanine, and adenine bases the lowest energy conformer is C2′-endo/anti, whereas in 2′- deoxycytidine the most stable conformer is C3′-endo/anti. In ribonucleosides, the C3′-endo/anti and C2′- endo/anti conformers nearly have the same energy, except in cytidine, where the most stable conformer is C3′-endo/anti. Therefore, a general discussion has been devoted to the exceptional cases of 2′-deoxycytidine and cytidine compared to the other nucleosides. The present calculated results have also been compared with those recently reported at the MP2 level by other authors on the 2′-deoxyribonucleosides or smaller model compounds on one hand, and with the experimental results based on a statistical survey of nucleoside crystal structures on the other hand. I. Introduction Analysis of the structural properties of nucleic acid constitu- ents is a fundamental task to understand their biological functions. This task can be partly achieved by studying the energetic and conformational properties of the elementary building blocks of the nucleic acids, i.e., nucleosides and nucleotides. Recently, in the first paper of this series, 1 we analyzed the ground-state properties of ribonucleosides and ribonucleotides, such as uridine, cytidine, 5′-methyl phosphate uridine, and 3′- methyl phosphate uridine, which can be considered as RNA building blocks. The energy and geometry 1 of these moieties as well as the harmonic vibrations 2 of uridine and cytidine have been estimated at the density functional level of theory. On the basis of the above-mentioned theoretical investigations 1,2 and previous reports on the same subject, 3,4 one can conclude that the density functional theory (DFT) calculations performed by means of the hybrid exchange and correlation functional (Becke-Lee-Parr, B3LYP) and sufficiently extended basis functions, such as 6-31G*, can now be regarded as a cost- effective alternative to the sophisticated and time-consuming MP2 (second-order perturbative Moller-Plesset method), as far as the analysis of the ground-state properties of nucleic acid constituents is concerned. To our knowledge, a complete set of theoretical calculations including electronic correlation effects concerning the energy and geometry of all the ribonucleosides and 2 ′-deoxyribonucleo- sides containing the four major nucleic acid bases are still lacking in the literature. Thus, in this paper, our aim is to report the results concerning adenosine and guanosine, completing the main results of the previous investigations on uridine and cytidine, 1 as well as those corresponding to all four major 2′- deoxyribonucleosides (building blocks of DNA) at the DFT/ B3LYP/6-31G (/) level of theory. The only existing theoretical results at the MP2/6-31G* level of theory on 2′-deoxyribo- nucleosides with an anti orientation of the base with respect to the sugar 5 as well as those on smaller nucleoside model compounds 6,7 have been carefully overviewed in the present paper and used here for comparison. The comparison between the calculated and experimental results is based on the statistical analysis of nucleoside X-ray structures in the solid state. 8 II. Theoretical Details Figure 1 displays the atom numbering and chemical structure of the major 2′-deoxyribonucleosides and ribonucleosides. Each of these eight molecules has been defined by a -junction of one of the DNA bases (T, A, C, and G) or the RNA bases (U, A, C, and G) to a sugar, i.e., 2′-deoxyribose (in 2′-deoxyribo- nucleosides) and ribose (in ribonucleosides), respectively. For the sake of brevity, these molecules are hereafter referred to as * To whom correspondence should be addressed. Phone: +33-1- 44277555. Fax: +33-1-44277560. E-mail: ghomi@lpbc.jussieu.fr. 4560 J. Phys. Chem. B 2000, 104, 4560-4568 10.1021/jp994077p CCC: $19.00 © 2000 American Chemical Society Published on Web 04/14/2000