Molecular orbital calculations on the conformation of nucleic acids and their constituents VI. Conformation about the exocyclic C(4′)-C(5′) bond in α-nucleosides

Biochimica et Biophysica Acta, 299 (1973) 497-499 Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands BSA 97604

MOLECULAR ORBITAL CALCULATIONS ON THE CONFORMATION OF NUCLEIC ACIDS AND THEIR CONSTITUENTS VI. CONFORMATION ABOUT THE EXOCYCLIC C(4')--C(5') BOND IN ~-NUCLEOSIDES

ANIL SARAN, B E R N A R D P U L L M A N and DAVID P E R A H I A lnstitut de Biologie Physico-Chimique, Laboratoire de Biochimie Thdorique associd au C.N.R.S., 13, rue P. et M. Curie, Paris 5~ (France) (Received November 13th, 1972)

SUMMARY

PCILO (Perturbative Configuration Irtteraction using Localized Orbitals) computations carried out for the conformation of the exocyclic C(4')-C(5') bond in ~-nucleosides with the C(2')-exo and C(Y)-exo puckers of the sugar predict the gg conformation to be the most stable one. This result, which is in agreement with recent NMR studies in solution, brings additional evidence to the conclusions of an exhaustive recent study of the fl-nucleosides 4, in which it was proposed that the existence of some nucleosides in the crystal in the gt or tg conformations may reasonably be attributed to the effect of environmental forces.

In our series of studies by the quantum-mechanical PCILO (Perturbative Configuration Interaction using Localized Orbitals) method on the conformation of nucleic acids and their constituents t -5, we presented recently a detailed investigation of the conformation of the exocyclie C(4')-C(5') bond in fl-nucleosides 4. This note presents an extension of this last study to ~-nucleosides having C(2')-exo and C(3')exo sugar puckers. The definitions and notations of the torsion angles are the same as in ref. 4. All the hydrogen atoms have been taken into account. Their bond and dihedral angles have been kept in the crystallographic conformations but the C-H bond distances have been uniformly fixed at 1A. The conformational energy maps have been constructed as a function of the torsions about the angles q~c~¢,)-c~5,) and ~c~5"~-o~5,), the computations being carried out in 30 ° increments of the angles. The presentation of the results on the conformational energy maps has been limited to 3 kcal/mole above the global minimum isoenergy curve. ~-Pseudouridine has been chosen as a representative compound of C(2')-exo~-nucleosides. The geometrical input data for this molecule come from the crystal structure studies of Rohrer and Sundaralingam6. The results of the calculations are

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presented in Fig. 1. The map shows a global minimum in the 99 region at ~c(4,)-c(5,) = 60 ° and ~c(s')-o(s')= 300 °. The 9t (~c(4,)-c(s,)= 180 °) and t9 (~c(4,)-c(5,)= 300 °) conformations, also associated with ~c(s')-o(5') = 300 °, are both 1 kcal/mole above the gg conformation. There is a large area of stability, only 0.5 kcal/mole above the global minimum, associated with the ~# conformation for 4~c(5,).o(s,) varying from 175 ° to 335 ° 3so

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Fig. 1. Conformational energy map for ~-pseudouridine. Isoenergy curves with respect to the global minimum taken as energy zero. Fig. 2. Conformational energy map for ~-D-2"-amino-2'-deoxyadenosine.Isoenergy curves with respect to the global minimum taken as energy zero. The crystallographic conformation of 0c-pseudouridine is gt with q~c(4')-c(5') = 189.7 ° and ~ct5')-o(5')= 296.9 °. It falls thus within the 1 kcal/mole theoretical isoenergy curve associated with this secondary energy minimum. N M R studies in solution 7-1° indicate, however, that 0t-(and fl-)pseudouridines exist predominantly in the g9 conformation, although the yt and t9 rotamers ale also appreciably populated. As already discussed in ref. 4 in connection with similar discrepancies in the cases of dihydrouridine and C(3')-exo-fl-nucleosides, the situation in solution being more comparable to the computed one, the results speak in favor of the genuine correctness of the PCILO evaluation. We consider thus the g9 conformation as being fundamentally the most stable one for ~-pseudouridine and the departure from this conformation in the crystal as being due to the action of the packing forces. It may be added that three more compounds belonging to the C(2')-exo-0c-nucleosides have been studied crystallographically. These are: vitamin B12 wet 11, vitamin B12 air dry 12 and vitamin Btz 5'-phosphate 13. The three compounds occur in the crystal in the g9 conformation with q~c(4')-c(5')equal to 74 °, 66 ° and 53 °, respectively. As concerns the C(Y)-exo nueleosides, the compound chosen for the computation is ~-D-2'-amino-2'-deoxyadenosine whose crystal structure has been determined by Rohrer and Sundaralingam 14. The results of the calculations are presented in Fig. 2. The conformational energy map shows a global minimum for the g9 conformation with 4ic(4,).c(5,) = 60 ° and ~c(5')-ots')= 180°. There is a large area included within the 1 kcal/mole isoenergy curve associated with the global minimum. The 9t (~c(4,)-c(s,) = 180 °) and the tg (~c(4')-ecs') = 300 °) conformations are, respecti-

EXOCYCLIC C(4")-C(5') BOND IN ~t-NUCLEOSIDES

499

rely, 2 and 3 kcal/mole higher than the gg conformation. The crystallographic conformation 14 for this compound is gt with ~c(4,)-c(s,)= 171.2 ° and ¢c(s,)-o~s,)= 101.3 o. It falls within the 3 kcal/mole isoenergy curve of this secondary minimum. Unfortunately, no N M R studies in solution are available for this compound. The situation is, however, very similar to that for the C(3')-exo-/~-deoxyadenosine for which the calculations also predict the gg conformation as the most stable one 4 while the crystallographic conformation is gt, (theoretically 4 kcal/mole above the gg) but for which N M R studies in solution 1s, 16 confirm the predominance of the 99 conformer. Our prediction would thus be again that the gg conformer is intrinsically the most stable one for a-D-2'-amino-2'-deoxyadenosine and that it may possibly be observed as the predominant one in solution. There is another compound of the C(3')-exo-ct-nucleoside series whose crystal structure is known: 5-[1-(2'-deoxy-a-o-ribofuranosyl)]uracilyl disulfide I 7. It has two molecules in the crystalline asymmetric unit: molecule 1 is in the tg (~c(4")-c~s,) = 290 °) conformation whereas molecule 2 is in the gg (Cbc(4,).c(s,) = 68 °) conformation. In conclusion, it may be said that the present results enlarge the field of application of our proposal that the gO conformation is fundamentally the most stable one for the overwhelming majority of nucleosides, if not for all of them, whether ct or fl, associated with the common C(2')-endo, C(3')-endo, C(2')-exo and C(3')-exo sugar puckers. We attribute the occurrence of some of these compounds in the crystal (and possibly in some solvents) in the gt or tg conformations to the effect of environmental forces. REFERENCES 1 2 3 4 5 6 7 8 9 l0 I1 12 13 14 15 16 17

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