Conformational Properties of the Deoxyribose and Ribose Moieties of Nucleic Acids: a Quantum Mechanical Study

J. Phys. Chem. B 1998, 102, 6669-6678 6669 Conformational Properties of the Deoxyribose and Ribose Moieties of Nucleic Acids: A Quantum Mechanical Study Nicolas Foloppe and Alexander D. MacKerell, Jr.* Department of Pharmaceutical Sciences, School of Pharmacy, UniVersity of Maryland, Baltimore, Maryland 21201 ReceiVed: April 15, 1998 The present work analyzes the intrinsic conformational energetics associated with the puckering of the deoxyribose and ribose sugars in nucleic acids using high-level ab initio quantum mechanical calculations. A variety of model compounds have been designed to define the minimal structural unit suitable to model the sugar moiety in nucleic acids. Results suggest that all the structural features of a nucleoside are required to model the sugar moiety of nucleic acids. Stuctures calculated at the MP2 level of theory are in close agreement with experimental structural information. In deoxyribose, the south pucker (B form of double helices) is intrinsically favored over the north pucker (A form of double helices) by ∼1.0 kcal/mol. In contrast, for ribose, with torsion in an RNA-like conformation, the north pucker is favored over the south pucker by ∼2.0 kcal/mol. For both the deoxyribose and ribose of nucleic acids, the lowest energy barrier between the north and south puckers is >4.0 kcal/mol. The present calculations suggest that crossing this barrier may involve a decrease in the amplitude of the furanose ring. Implications of these results with respect to nucleic acid stucture and dynamics are discussed. 1. Introduction modate both conformations.8,9 However, condensed phase structural information from experimental approaches includes It is now well documented that nucleic acid structural possible contributions from solvent effects, crystal packing 1 variability and flexibility is related to their biological functions. interactions, or other internal degrees of freedom in the The sugar moiety occupies a central position in the structure of molecules investigated. It is thus difficult to derive the intrinsic nucleic acids, and is of crucial importance in shaping their energetic properties of the ribose or deoxyribose solely from structure and dynamics. This importance is evidenced by the statistical analysis of the condensed phase structures containing striking differences in structural properties between DNA and these moieties. Improved knowledge of the contributions of RNA, which differ only by the chemical nature of their sugar. the sugar moiety to nucleic acids energetics is, however, of Although DNA and RNA differ only by a hydroxyl group, it is general interest to better understand the conformational proper- enough to confine RNA double helices to a single structural ties of DNA and RNA. family (A form), whereas DNA is polymorphic and exists in a 1 Another limitation of available experimental data concerning variety of structural families including the A, B, and Z forms. the sugar conformational properties is their being mostly The pivotal role of the sugar in nucleic acids structures is further restricted to the north and south regions. Measurements in illustrated by the direct relationship between the deoxyribose 3,5,6,10 2 solution suggest that in nucleosides and nucleotides, as ring conformation and the overall structure of the DNA. well as in DNA,11-14 the sugar exists in a dynamic equilibrium The sugar ring conformation, or puckering, can be conve- between the north and south conformations. Consequently, the niently described by two parameters, the pseudorotation angle height of the energy barrier between the north and south energy 3 and the amplitude of pucker. In the structures of nucleosides minima of the furanose ring is expected to play an important 4-7 2 and nucleotides, as well as oligonucleotides, the sugar role in governing the dynamic behavior of the nucleic acids pseudorotation angle has been found to populate essentially two and their components. As noted earlier,9 the barrier associated ranges of conformations, referred to as the north and the south with the east quadrant is expected to lie between 2.0 and 5.0 3 ranges. The north range is associated with RNA and the A kcal/mol above the global energy minimum. The lower estimate form of DNA, and the south range is associated with the B is deduced from the scarcity of structures detected experimen- form of DNA. In the Z form of DNA, the sugar is found in tally with a pseudorotation angle falling in the east quadrant, 2 both the north and south ranges. whereas the higher estimate is compatible with the expected Although experimental approaches have yielded a wealth of interconversion between the north and south puckers at room information concerning the conformations accessible to the sugar temperature. Ro¨der et al.10 found a barrier of 4.7 ( 0.5 kcal/ in nucleic acids and its components, the relationship between mol for purine ribosides in deuteroammonia, although the these conformations and the intrinsic energetics of the sugar relevance of this result to biological situations may be questioned remains unclear. For both ribose and deoxyribose, the energy given the solvent used. To our knowledge, an equivalent study difference between the north and south conformations is for deoxyribo-containing compounds is not available. expected to be small enough to allow these sugars to accom- Theoretical calculations can complement experimental methods and provide further insights regarding the intrinsic energetics * To whom correspondence should be addressed. of the sugar in nucleic acids, independently of condensed phase S1089-5647(98)01868-9 CCC: $15.00 © 1998 American Chemical Society Published on Web 08/05/1998 6670 J. Phys. Chem. B, Vol. 102, No. 34, 1998 Foloppe and Mackerell effects, and on the entire range of pseudorotation angle values. To date, theoretical studies of the sugars in nucleic acids have been limited to semiempirical quantum mechanical15 or empirical force field investigations.8,16 Olson and Sussman9 have already discussed some discrepancies between the large body of experimental data pertaining to the sugars in nucleic acids and the results of Saran et al.15 and Levitt and Warshel.16 Olson8 has derived a potential parametrized to be compatible with experimentally observed populations in the north and south energy minima. That work stressed the usefulness of the gauche effect to explain the influence of the furanose substituents on the sugar conformational properties. The developed potential, however, remains empirical in nature and its validity for regions of the pseudorotation angle for which experimental data are scarce or nonexistent is an open question. In the present work, the conformational energetics of model compounds containing deoxyribose or ribose are examined using high-level quantum chemical calculations. Comparison of the results from the present calculations with available experimental data suggests that all the structural features of a nucleoside are required to model the sugar moiety in nucleic acids. In such a model, the deoxyribose south conformation is intrinsically more stable than the north, but the energy difference between the north and south conformations is small enough to allow for the existence of the north conformation. In contrast, the corre- sponding energy difference in the ribose, when is restricted to an RNA-like conformation, favors the north conformation and makes the south conformation unlikely. In addition, the Figure 1. Model compounds A, B, C, and D used to model present calculations provide a powerful alternative to experi- deoxyribose and model compound E used to model ribose. mental methods to probe the energy barriers between the north and south energy minima. For both deoxyribose and ribose, sets for the neutral and anionic compounds, respectively. All the present calculations suggest a significant potential energy pseudorotation energy surfaces were investigated at both the barrier between the north and south energy minima. A marked restricted Hartree-Fock (HF) level of theory and at the second- flattening of the furanose ring is observed when crossing the order Møller-Plesset (MP2) level of theory, except for com- energy barrier between these two energy minima. pounds D and E. For compound D, calculations were performed The present results will be useful to improve the calibration only at the HF level and for compound E they were performed of the sugar conformational properties in nucleic acid force only at the MP2 level. fields. Pseudorotation energy surfaces were obtained by fixing one endocyclic dihedral angle and performing energy minimization. 2. Methods For compounds A, B, C, and E, the dihedral C1′-C2′-C3′- C4′ was fixed at 10.0° increments from -30.0 to 30.0°. For Structures of the model compounds used to explore the compounds A, B, and D, the C3′ endo and C2′ endo conforma- deoxyribose and ribose pseudorotation properties are shown in tions were obtained by fixing the dihedral angles C4′-O4′- Figure 1. Throughout the present work each model compound C1′-C2′ and C3′-C4′-O4′-C1′ to 0.0°. For each pseudo- will be referred to by its letter designation. The nucleic acid rotation energy surface, both the south and north energy minima atom names and dihedral angle nomenclature1 is used for their were located by relaxing all constraints on the furanose model compounds counterparts. Accordingly, the dihedral endocyclic torsions. Energy surfaces were offset relative to their angles are defined as follows: global energy minimum and are presented as a function of the â γ δ ú pseudorotation angle. The pseudorotation angles and amplitudes H O5′ C5′ C4′ C3′ O3′ HorP were extracted from the energy minimized structures. The energy barrier between two energy minima is defined here as In all the model compounds except A, the base is modeled by the energy difference between the global energy minimum and an imidazole moiety because it is computationaly more tractable the point of highest energy obtained by discrete sampling than any of the natural bases present in nucleic acids.

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