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Albany 2001

category image Biomolecular
Stereodynamics
SUNY at Albany
June 19-23, 2001

An ab Initio Study of the cis-syn Cyclobutane Pyrimidine Dimers and a Tautomer-Bypass Mechanism for the Origin of UV-Induced Mutations

A quantum mechanical study of all cys-syn cyclobutane pyrimidine photodimers (Pyr[ ]Pyr) including the normal (amino form for Cyt and lactam form for Thy and Ura) and rare (imino form for Cyt and lactim form for Thy and Ura) tautomeric forms of bases has been performed using the ab initio method at HF/6-31G(d,p), MP2(fc)//HF/6-31G(d,p) and MP2(fc)/6-31G(d,p) levels. The rare tautomers of Cyt and Thy and Ura were considered in the trans and cis conformations, respectively, since these conformers are important because of their possible role in point mutagenesis. It is shown that the cyclobutyl ring is folded with a puckering angle of 16-21* for most of the dimers and a value of 159-163* for a few. The amount of twist measured by the torsion angle around the C(5)?C(5?) bond for dimers is 14-28* and 151-157*. The puckering and torsion angles are in a good agreement with available experimental data. It is predicted that in the gas phase all photodimers containing the imino form of Cyt (Cyt*) are more stable than those containing its amino form. An order of the stability for the Cyt*-containing dimers obtained by the HF/6-31G(d,p) method is: Cyt*[ ]Cyt* (-10.16 Kcal/mol) > Cyt[ ]Cyt* (-5.86 Kcal/mol) > Ura[ ]Cyt* (-4.09 Kcal/mol) > Thy[ ]Cyt* (-3.93 Kcal/mol). In contrast with the prediction for the Cyt-containing dimers, the comparison of the relative stabilization energies for the Thy- and/or Ura- containing dimers shows that their preferable form is the normal (lactam) form of the corresponding bases. The Monte Carlo simulations show that the Cyt[ ]Cyt dimer containing the imino form(s) of cytosine is more stabilized by a water cluster than those containing its amino form(s). The possible biological significance stems from the fact that the Cyt in the dimer directs the incorporation of Ade in the complementary strand during replication. Data obtained point to the Cyt tautomerism as a possible mechanism for the origin of UV-induced mutation.

V. I. Danilov (1), A. Les (2), J. L. Alderfer (3)*

(1)Inst./Mol. Biol./Genetics, Kiev-143, 03143 Ukraine (2)Dep't./Chem., Univ. of Warsaw, 02-093 Warsaw, Poland (3)Roswell Park Cancer Inst., Buffalo, N.Y. 14263-0001 U.S.A. *Ph: (716) 845- 4471; F: (716) 845-3475; email: James.Alderfer@RoswellPark.org