Relating Macromolecular Function and Association: The Structural Basis of Protein-DNA and RNA Recognition

The interaction between proteins and DNA or RNA plays an essential part in the function of biological macromolecules, and its physical basis resides in the three-dimensional structure of the interfaces that they form. We analyze the geometric, chemical and physical chemical properties of the interfaces that occur in sets of protein DNA and protein-RNA complexes issued from X-ray studies and deposited in the Protein Data Bank. The interface size is measured by the area of the molecular surface buried in the contact. The average protein-DNA (resp. RNA) interface buries 3180 A 2 ( resp. 2530 A 2) of the surface of the component molecules, and involves 49 ( resp. 43) amino acid residues and 24 ( resp. 18) nucleotides. The formation of an interface that buries 3000 A 2 or more of the protein and nucleic acid surfaces, is often accompanied with conformation changes that affect one or both components. The smallest interfaces bury about 900 A 2; they involve about 15 amino acids and 6-7 nucleotides in a double helix, but only 3 or 4, in an extended segment. The protein surface in contact with the nucleic acid has a peculiar amino acid composition, it is highly polar and bears a uniform positive charge complementary to the nucleic acid surface. Protein nucleic acid interfaces contain many polar interactions, either direct H-bonds or salt bridges, or H-bonds mediated by water molecules. The average protein-DNA interface contains 22 direct polar interactions, 60% of which involve the phosphate groups; the average protein-RNA interfaces contains 20, 35% of them with the phosphates and 25% with the 2'-OH of the ribose. About one-third of the interface H-bonds implicate the bases of both DNA and RNA, but protein-DNA complexes exhibit specific patterns that are not observed with RNA. An example is the recognition of a G: C pair by a Lys or Arg side chain located in the major groove of the double helix. The atoms buried at the interfaces are close-packed, which indicates that they belong to surfaces with complementary shapes. Thus, protein-nucleic acid recognition involves elements of shape recognition as well as electrostatic interaction and the recognition of the base sequence.