title: Energetic basis for selective recognition of T*G mismatched base pairs in DNA by imidazole-rich polyamides.
abstract: To complement available structure and binding results and to develop a detailed understanding of the basis for selective molecular recognition of T.G mismatches in DNA by imidazole containing polyamides, a full thermodynamic profile for formation of the T.G-polyamide complex has been determined. The amide-linked heterocycles f-ImImIm and f-PyImIm (where f is formamido group, Im is imidazole and Py is pyrrole) were studied by using biosensor-surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) with a T.G mismatch containing DNA hairpin duplex and a similar DNA with only Watson-Crick base pairs. Large negative binding enthalpies for all of the polyamide-DNA complexes indicate that the interactions are enthalpically driven. SPR results show slower complex formation and stronger binding of f-ImImIm to the T.G than to the match site. The thermodynamic analysis indicates that the enhanced binding to the T.G site is the result of better entropic contributions. Negative heat capacity changes for the complex are correlated with calculated solvent accessible surface area changes and indicate hydrophobic contributions to complex formation. DNase I footprinting analysis in a long DNA sequence provided supporting evidence that f-ImImIm binds selectively to T.G mismatch sites.
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Eilyn R
authors.initials: ER
authors.lastname: Lacy
authors.forename: Binh
authors.initials: B
authors.lastname: Nguyen
authors.forename: Minh
authors.initials: M
authors.lastname: Le
authors.forename: Kari K
authors.initials: KK
authors.lastname: Cox
authors.forename: Caroline
authors.initials: C
authors.lastname: OHare
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
authors.forename: Moses
authors.initials: M
authors.lastname: Lee
authors.forename: W David
authors.initials: WD
authors.lastname: Wilson
mesh_terms: D020137:Base Pair Mismatch; D001483:Base Sequence; D001665:Binding Sites; D002151:Calorimetry; D004247:DNA / Q000737:chemistry; D018983:DNA Footprinting; D006147:Guanine / Q000378:metabolism*; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism*; D009757:Nylons / Q000737:chemistry; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism*; D020349:Surface Plasmon Resonance; D013816:Thermodynamics; D013941:Thymine / Q000378:metabolism*
chemical_list: D007093:Imidazoles; C487889:N-(2-(dimethylamino)ethyl)-1-methyl-4-(1-methyl-4-(4-formamido-1-methylimidazole-2-carboxamide)imidazole-2- carboxamido)imidazole-2-carboxamide; C487888:N-(2-(dimethylamino)ethyl)-1-methyl-4-(1-methyl-4-(4-formamido-1-methylpyrrole-2-carboxamido)imidazole-2-carboxamido)imidazole-2-carboxamide; D009757:Nylons; D011758:Pyrroles; D006147:Guanine; D004247:DNA; D013941:Thymine