Do water molecules mediate protein-DNA recognition?

A comprehensive analysis of interfacial water molecules in the structures o f 109 unique protein-DNA complexes is presented together with a new view on their role in protein-DNA recognition. Location of interfacial water molec ules as reported in the crystal structures and as emerging from a series of molecular dynamics studies on protein-DNA complexes with explicit solvent and counterions, was analyzed based on their acceptor, donor hydrogen bond relationships with the atoms and residues of the macromolecules, electrosta tic field calculations and packing density considerations. Water molecules for the purpose of this study have been categorized into four classes: viz. (I) those that contact both the protein and the DNA simultaneously and thu s mediate recognition directly; (II) those that contact either the protein or the DNA exclusively via hydrogen bonds solvating each solute separately; (HI) those that contact the hydrophobic groups in either the protein or th e DNA; and, lastly (IV) those that contact another water molecule. Of the 1 7,963 crystallographic water molecules under examination, about 6% belong t o class I and 76% belong to class II. About three-fourths of class I and cl ass Il water molecules are exclusively associated with hydrogen bond accept or atoms of both protein and DNA. Noting that DNA is polyanionic, it is sig nificant that a majority of the crystallographically observed water molecul es as well as those from molecular dynamics simulations should be involved in facilitating binding by screening unfavorable electrostatics. Less than 2% of the reported water molecules occur between hydrogen bond donor atoms of protein and acceptor atoms of DNA. These represent cases where protein a toms cannot reach out to DNA to make favorable hydrogen bond interactions d ue to packing/structural restrictions and interfacial water molecules provi de an extension to side-chains to accomplish hydrogen bonding. (C) 2001 Aca demic Press.