DAPI binding to the DNA minor groove: A continuum solvent analysis

L. F. Pineda De Castro, M. Zacharias

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

A continuum solvent model based on the generalized Born (GB) or finite-difference Poisson-Boltzmann (FDPB) approaches has been employed to compare the binding of 4′-6-diamidine-2-phenyl indole (DAPI) to the minor groove of various DNA sequences. Qualitative agreement between the results of GB and FDPB approaches as well as between calculated and experimentally observed trends regarding the sequence specificity of DAPI binding to B-DNA was obtained. Calculated binding energies were decomposed into various contributions to solvation and DNA-ligand interaction. DNA conformational adaptation was found to make a favorable contribution to the calculated total interaction energy but did not change the DAPI binding affinity ranking of different DNA sequences. The calculations indicate that closed complex formation is mainly driven by nonpolar contributions and was found to be disfavored electrostatically due to a desolvation penalty that outbalances the attractive Coulomb interaction. The calculated penalty was larger for DAPI binding to GC-rich sequences compared with AT-rich target sequences and generally larger for the FDPB vs the GB continuum model. A radial interaction profile for DAPI at different distances from the DNA minor groove revealed an electrostatic energy minimum a few Angstroms farther away from the closed binding geometry. The calculated electrostatic interaction up to this distance is attractive and it may stabilize a nonspecific binding arrangement.

Original languageEnglish
Pages (from-to)209-220
Number of pages12
JournalJournal of Molecular Recognition
Volume15
Issue number4
DOIs
StatePublished - Jul 2002
Externally publishedYes

Keywords

  • Docking
  • Force field calculations
  • Generalized Born equation
  • Nucleic acid-ligand interaction
  • Poisson-Boltzmann equation
  • Sequence specificity

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