title: Estimation of the DNA sequence discriminatory ability of hairpin-linked lexitropsins.
abstract: Three- and four-ring polyamides containing N-methylimidazole and N-methylpyrrole, and their hairpin-linked derivatives, bind side-by-side in the minor groove of DNA in a sequence-specific manner. The sequences recognized by side-by-side molecules are dependent on the pairings of the polyamide rings to the bases. In this study we report a mathematical model for estimating the free energies of binding for gamma-aminobutyric acid-linked polyamides to 5- and 6-bp DNA sequences. The model parameters are calibrated by a least-squares fit to 35 experimental binding constants. The model performs well in cross-validation experiments and the parameters are consistent with previously proposed empirical rules of polyamide-DNA binding. We apply the model to the design of targeted polyamides, evaluating the ability of the proposed polyamides to bind to a DNA sequence of interest while minimizing binding to the remaining DNA sequences.
authors.affiliation: Department of Biomathematics and the Molecular Biology Institute, University of California, Los Angeles, CA 90024, USA.
authors.forename: W L
authors.initials: WL
authors.lastname: Walker
authors.forename: E M
authors.initials: EM
authors.lastname: Landaw
authors.forename: R E
authors.initials: RE
authors.lastname: Dickerson
authors.forename: D S
authors.initials: DS
authors.lastname: Goodsell
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D001483:Base Sequence; D004247:DNA / Q000737:chemistry* / Q000378:metabolism*; D008956:Models, Chemical; D009429:Netropsin / Q000031:analogs & derivatives* / Q000737:chemistry; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D009838:Oligodeoxyribonucleotides; C053654:lexitropsin; D009429:Netropsin; D004247:DNA