title: Relative binding affinities of distamycin and its analog to d(CGCAAGTTGGC).d(GCCAACTTGCG): comparison of simulation results with experiment.
abstract: We report here an effort to use molecular dynamics/free energy perturbation methodology to calculate relative binding affinities of two related drugs to DNA. Specifically, we focus on the relative binding free energies of distamycin (Dst) and its analog, 2-imidazoledistamycin (2-ImD), to d(CGCAAGTTGGC).d(GCCAACTTGCG). The pyrrole (Dst) and the imidazole variant (2-ImD) differ only in that the C-H is substituted by an N in the central ring. The starting conformation for these calculations was the previously determined solution structure of two 2-ImD molecules in the minor groove of the above 11-residue DNA. In this complex both the ligands have the imidazole nitrogen (N3) oriented toward the amino group of G6. However only ligand 1 (site I) has N3 within the hydrogen bonding distance from N2 amino proton of G6. We have calculated the difference in free energy of binding of 2-ImD versus Dst in three different cases by mutating 2-ImD-->Dst reversibly. In the first case ligand 1 (site I) is mutated, in the second case ligand 2 (site II) is mutated, and in the third case both the ligands are mutated. These calculations show that at site I Dst has weaker binding affinity than 2-ImD by 0.7 kcal/mol, at site II Dst has stronger binding affinity than 2-ImD by 2.9 kcal/mol, and when occupying both site I and site II, Dst binds with greater affinity than 2-ImD by 1.8 kcal/mol. Recent experimental findings agree semiquantitatively (within 1 kcal/mol) with the calculations presented here. Hence the methodology presented here can be used to predict relative binding energies of two or more closely related molecules to DNA.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco 94143.
authors.forename: S B
authors.initials: SB
authors.lastname: Singh
authors.forename: D E
authors.initials: DE
authors.lastname: Wemmer
authors.forename: P A
authors.initials: PA
authors.lastname: Kollman
mesh_terms: D001483:Base Sequence; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004214:Distamycins / Q000737:chemistry* / Q000378:metabolism; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004214:Distamycins; D009838:Oligodeoxyribonucleotides; C088655:2-imidazoledistamycin; C088656:d(CGCAAGTTGGC).d(GCCAACTTGCG); C030000:stallimycin; D004247:DNA