title: Complex of B-DNA with polyamides freezes DNA backbone flexibility.
abstract: The development of sequence-specific minor groove binding ligands is a modern and rapidly growing field of research because of their extraordinary importance as transcription-controlling drugs. We performed three molecular dynamics simulations in order to clarify the influence of minor groove binding of two ImHpPyPy-beta-Dp polyamides to the d(CCAGTACTGG)(2) decamer in the B-form. This decamer contains the recognition sequence for the trp repressor (5'-GTACT-3'), and it was investigated recently by X-ray crystallography. On one hand we are able to reproduce X-ray-determined DNA--drug contacts, and on the other hand we provide new contact information which is important for the development of potential ligands. The new insights show how the beta-tail of the polyamide ligands contributes to binding. Our simulations also indicate that complexation freezes the DNA backbone in a specific B(I) or B(II) substate conformation and thus optimizes nonbonded contacts. The existence of this distinct B(I)/B(II) substate pattern also allows the formation of water-mediated contacts. Thus, we suggest the B(I) <==> B(II) substate behavior to be an important part of the indirect readout of DNA.
authors.affiliation: Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innrain 52a, A-6020 Innsbruck, Austria.
authors.forename: B
authors.initials: B
authors.lastname: Wellenzohn
authors.forename: W
authors.initials: W
authors.lastname: Flader
authors.forename: R H
authors.initials: RH
authors.lastname: Winger
authors.forename: A
authors.initials: A
authors.lastname: Hallbrucker
authors.forename: E
authors.initials: E
authors.lastname: Mayer
authors.forename: K R
authors.initials: KR
authors.lastname: Liedl
mesh_terms: D001483:Base Sequence; D004247:DNA / Q000737:chemistry*; D006860:Hydrogen Bonding; D009690:Nucleic Acid Conformation; D009757:Nylons / Q000737:chemistry*
chemical_list: D009757:Nylons; D004247:DNA