title: Thermodynamics of nucleic acid "shape readout" by an aminosugar.
abstract: Recognition of nucleic acids is important for our understanding of nucleic acid structure as well as for our understanding of nucleic acid-protein interactions. In addition to the direct readout mechanisms of nucleic acids such as H-bonding, shape recognition of nucleic acids is being increasingly recognized as playing an equally important role in DNA recognition. Competition dialysis, UV, flourescent intercalator displacement (FID), computational docking, and calorimetry studies were conducted to study the interaction of neomycin with a variety of nucleic acid conformations (shapes). At pH 5.5, the results suggest the following. (1) Neomycin binds three RNA structures [16S A site rRNA, poly(rA)·poly(rA), and poly(rA)·poly(rU)] with high affinities (K(a) ~ 10(7) M(-1)). (2) The binding of neomycin to A-form GC-rich oligomer d(A(2)G(15)C(15)T(2))(2) has an affinity comparable to those of RNA structures. (3) The binding of neomycin to DNA·RNA hybrids shows a 3-fold variance that can be attributed to their structural differences [for poly(dA)·poly(rU), K(a) = 9.4 × 10(6) M(-1), and for poly(rA)·poly(dT), K(a) = 3.1 × 10(6) M(-1)]. (4) The interaction of neomycin with DNA triplex poly(dA)·2poly(dT) yields a binding affinity (K(a)) of 2.4 × 10(5) M(-1). (5) Poly(dA-dT)(2) shows the lowest association constant for all nucleic acids studied (K(a) < 10(5)). (6) Neomycin binds to G-quadruplexes with K(a) values of ~10(4)-10(5) M(-1). (7) Computational studies show that the decrease in major groove width in the B to A transition correlates with increasing neomycin affinity. Neomycin's affinity for various nucleic acid structures can be ranked as follows: RNAs and GC-rich d(A(2)G(15)C(15)T(2))(2) structures > poly(dA)·poly(rU) > poly(rA)·poly(dT) > T·A-T triplex, G-quadruplex, B-form AT-rich, or GC-rich DNA sequences. The results illustrate the first example of a small molecule-based "shape readout" of different nucleic acid conformations.
authors.affiliation: Laboratory of Medicinal Chemistry, Department of Chemistry, Clemson University, Clemson, South Carolina 29634, United States.
authors.forename: Hongjuan
authors.initials: H
authors.lastname: Xi
authors.forename: Erik
authors.initials: E
authors.lastname: Davis
authors.forename: Nihar
authors.initials: N
authors.lastname: Ranjan
authors.forename: Liang
authors.initials: L
authors.lastname: Xue
authors.forename: David
authors.initials: D
authors.lastname: Hyde-Volpe
authors.forename: Dev P
authors.initials: DP
authors.lastname: Arya
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D004247:DNA / Q000737:chemistry; D044704:DNA, A-Form / Q000737:chemistry; D059371:DNA, B-Form / Q000737:chemistry; D005452:Fluoresceins / Q000737:chemistry; D009355:Neomycin / Q000737:chemistry* / Q000378:metabolism; D009690:Nucleic Acid Conformation; D009692:Nucleic Acid Heteroduplexes / Q000737:chemistry; D009696:Nucleic Acids / Q000737:chemistry*; D010303:Paromomycin / Q000737:chemistry; D011119:Polynucleotides / Q000737:chemistry; D012271:Ribostamycin / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D000617:Aminoglycosides; D044704:DNA, A-Form; D059371:DNA, B-Form; D005452:Fluoresceins; D009692:Nucleic Acid Heteroduplexes; D009696:Nucleic Acids; D011119:Polynucleotides; D012271:Ribostamycin; D010303:Paromomycin; D004247:DNA; C427203:calf thymus DNA; D009355:Neomycin