title: Solution structure of an oligodeoxynucleotide duplex containing the exocyclic lesion 3,N4-etheno-2'-deoxycytidine opposite 2'-deoxyadenosine, determined by NMR spectroscopy and restrained molecular dynamics.
abstract: The d(C-G-T-A-C-epsilon C-C-A-T-G-C).d(G-C-A-T-G-A-G-T-A-C-G) oligodeoxynucleotide duplex containing the 3, N4-etheno-2'-deoxycytidine adduct positioned opposite 2'-deoxyadenosine in the center of the helix has been analyzed by proton NMR spectroscopy and restrained molecular dynamics. The spectroscopic data establish a right-handed duplex, with sugar puckers in the C2'-endo/C3'-exo range, residues adopting an anti conformation around the glycosidic torsion angle and, with the exception of epsilon C.dA, Watson-Crick hydrogen bond alignment for all base pairs. Molecular dynamics simulations, restrained by the full relaxation matrix approach, produced a three-dimensional model with an NMR R-factor of 7%. The duplex structure shows no significant perturbation of the sugar-phosphate backbone, which remains in B-form. The exocyclic adduct and its partner dA are incorporated into the helix without producing a noticeable kink. The epsilon C.dA alignment adopts a staggered conformation with each residue displaced toward the 5'-terminus and intercalated between bases on the opposite strand, without increase of inter-phosphate distances. The partial intercalation of the epsilon C (anti).dA(anti) alignment allows stacking between the aromatic rings of epsilon C and dA and with base pairs adjacent to the lesion, suggesting an important role played by hydrophobic forces in the stabilization of the solution structure.
authors.affiliation: Department of Pharmacological Sciences, State University of New York at Stony Brook 11794-8651, USA.
authors.forename: A
authors.initials: A
authors.lastname: Korobka
authors.forename: D
authors.initials: D
authors.lastname: Cullinan
authors.forename: M
authors.initials: M
authors.lastname: Cosman
authors.forename: A P
authors.initials: AP
authors.lastname: Grollman
authors.forename: D J
authors.initials: DJ
authors.lastname: Patel
authors.forename: M
authors.initials: M
authors.lastname: Eisenberg
authors.forename: C
authors.initials: C
authors.lastname: de los Santos
mesh_terms: D001482:Base Composition; D001483:Base Sequence; D003839:Deoxyadenosines / Q000737:chemistry*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry*; D011522:Protons; D012996:Solutions; D013816:Thermodynamics
chemical_list: D003839:Deoxyadenosines; D009838:Oligodeoxyribonucleotides; D011522:Protons; D012996:Solutions; D003841:Deoxycytidine; C032222:3,N(4)-ethenodeoxycytidine; C058118:2'-deoxyadenosine