Structural Features of Protein−Nucleic Acid Recognition Sites

Abstract

We analyzed the atomic models of 75 X-ray structures of protein-nucleic acid complexes with the aim of uncovering common properties. The interface area measured the extent of contact between the protein and nucleic acid. It was found to vary between 1120 and 5800 A2. Despite this wide variation, the interfaces in complexes of transcription factors with double-stranded DNA could be broken up into recognition modules where 12 +/- 3 nucleotides on the DNA side contact 24 +/- 6 amino acids on the protein side, with interface areas in the range 1600 +/- 400 A2. For enzymes acting on DNA, the recognition module is on average 600 A2 larger, due to the requirement of making an active site. As judged by its chemical and amino acid composition, the average protein surface in contact with the DNA is more polar than the solvent accessible surface or the typical protein-protein interface. The protein side is rich in positively charged groups from lysine and arginine side chains; on the DNA side the negative charges from phosphate groups dominate. Hydrogen bonding patterns were also analyzed, and we found one intermolecular hydrogen bond per 125 A2 of interface area in high-resolution structures. An equivalent number of polar interactions involved water molecules, which are generally abundant at protein-DNA interfaces. Calculations of Voronoi atomic volumes, performed in the presence and absence of water molecules, showed that protein atoms buried at the interface with DNA are on average as closely packed as in the protein interior. Water molecules contribute to the close packing, thereby mediating shape complementarity. Finally, conformational changes accompanying association were analyzed in 24 of the complexes for which the structure of the free protein was also available. On the DNA side the extent of deformation showed some correlation with the size of the interface area. On the protein side the type and size of the structural changes spanned a wide spectrum. Disorder-to-order transitions, domain movements, quaternary and tertiary changes were observed, and the largest changes occurred in complexes with large interfaces.

3DNA: a versatile, integrated software system for the analysis, rebuilding and visualization of three-dimensional nucleic-acid structures

“…That is, the deformations of helical structure occur in the context of the water molecules, proteins, and other species in direct contact with the double helix. Prior to our work, analyses of such interactions were literal and statistical in the sense of counting the number of different contacts in known structures 13,14 , or protein-centric in the sense of cataloging the various amino acids and folding motifs in close contact with nucleic acid [15][16][17][18] . Many of the tools developed to visualize protein-DNA complexes, e.g., NUCPLOT 19 , similarly focus on the identities of amino acids or secondary structural elements with respect to DNA primary structure.…”

G‐LoSA: An efficient computational tool for local structure‐centric biological studies and drug design

“…2 Proteinnucleic acid interactions are also crucial in biological processes, ranging from replication and transcription to enzymatic events to miRNA machinery. [3][4][5] Drug compounds bind to proteins, regulating their functions so as to acquire beneficial effects to treat diseases.…”

Protein–DNA Electrostatics

“…This supports the idea that electrostatics is involved to some extent in the intermittent behavior, with a probable role for the dissolved salt ions. Electrostatics plays indeed a major role in the protein-DNA interaction [14,15,16,17,18,19,20]. The reason is that DNA is very strongly negatively charged (-2 charges per base pair).…”

“…The reason is that DNA is very strongly negatively charged (-2 charges per base pair). On the other hand, DNA-binding proteins are most often positively charged on the surface that faces DNA, so to be attracted onto it [14,15].…”

“…This reading can be performed, besides other interactions, by the formation of hydrogen bonds between the protein and the side of the base pairs exposed toward the major groove, without opening the double helix [14,15]. Since the patterns of hydrogen bonds that may be formed on each base pair is different, a protein can discriminate precisely a target site by looking for the formation of the good hydrogen bond pattern along the entire sequence visited.…”