Sequence‐Specific Positions of Water Molecules at the Interface between DNA and Minor Groove Binders

• Published in: Chemphyschem Vol. 9; no. 18; pp. 2766 - 2771
• Main Authors: Spitzer, Gudrun M., Fuchs, Julian E., Markt, Patrick, Kirchmair, Johannes, Wellenzohn, Bernd, Langer, Thierry, Liedl, Klaus R.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY‐VCH Verlag 22.12.2008
• Subjects: Base Sequence; Binding Sites; DNA - chemistry; DNA recognition; drug design; Entropy; hydrogen bonds; Ligands; solvent effects; Water - chemistry
• ISSN: 1439-4235; 1439-7641
• DOI: 10.1002/cphc.200800647

Ligands able to specifically recognize DNA sequences are of fundamental interest as transcription‐controlling drugs. Herein, we analyze the positions of water molecules relative to B‐DNA base pairs in the minor groove of X‐ray and NMR protein data bank (PDB) structures. The patterns observed for water molecules at the interface between DNA and a ligand are compared with those obtained for structures without a ligand. Although the ligand end groups are often charged, and therefore highly hydrated, they do not alter the water patterns, which show considerable differences for the AT and CG base pairs. For AT they are much more precise than for CG in both ligand‐containing and ligand‐free structures. This behavior strongly indicates that the release of water molecules upon ligand binding leads to a gain of entropy and explains why this effect is especially pronounced for A‐tract B‐DNA sequences. Hydration of the minor groove plays an important role in ligand binding. For each DNA base pair, the positions of the water molecules—as well as those of their nearest neighbors—are determined from 3D structures and compared for complexed and ligand‐free DNA (see picture).