title: Bound water at protein-protein interfaces: partners, roles and hydrophobic bubbles as a conserved motif.
abstract: BACKGROUND
  There is a great interest in understanding and exploiting protein-protein associations as new routes for treating human disease. However, these associations are difficult to structurally characterize or model although the number of X-ray structures for protein-protein complexes is expanding. One feature of these complexes that has received little attention is the role of water molecules in the interfacial region.
  
  
  METHODS
  A data set of 4741 water molecules abstracted from 179 high-resolution (≤ 2.30 Å) X-ray crystal structures of protein-protein complexes was analyzed with a suite of modeling tools based on the HINT forcefield and hydrogen-bonding geometry. A metric termed Relevance was used to classify the general roles of the water molecules.
  
  
  RESULTS
  The water molecules were found to be involved in: a) (bridging) interactions with both proteins (21%), b) favorable interactions with only one protein (53%), and c) no interactions with either protein (26%). This trend is shown to be independent of the crystallographic resolution. Interactions with residue backbones are consistent for all classes and account for 21.5% of all interactions. Interactions with polar residues are significantly more common for the first group and interactions with non-polar residues dominate the last group. Waters interacting with both proteins stabilize on average the proteins' interaction (-0.46 kcal mol(-1)), but the overall average contribution of a single water to the protein-protein interaction energy is unfavorable (+0.03 kcal mol(-1)). Analysis of the waters without favorable interactions with either protein suggests that this is a conserved phenomenon: 42% of these waters have SASA ≤ 10 Å(2) and are thus largely buried, and 69% of these are within predominantly hydrophobic environments or "hydrophobic bubbles". Such water molecules may have an important biological purpose in mediating protein-protein interactions.
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Mostafa H
authors.initials: MH
authors.lastname: Ahmed
authors.forename: Francesca
authors.initials: F
authors.lastname: Spyrakis
authors.forename: Pietro
authors.initials: P
authors.lastname: Cozzini
authors.forename: Parijat K
authors.initials: PK
authors.lastname: Tripathi
authors.forename: Andrea
authors.initials: A
authors.lastname: Mozzarelli
authors.forename: J Neel
authors.initials: JN
authors.lastname: Scarsdale
authors.forename: Martin A
authors.initials: MA
authors.lastname: Safo
authors.forename: Glen E
authors.initials: GE
authors.lastname: Kellogg
mesh_terms: D000465:Algorithms; D020816:Amino Acid Motifs; D000596:Amino Acids / Q000737:chemistry / Q000145:classification / Q000378:metabolism; D016000:Cluster Analysis; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry / Q000378:metabolism; D012997:Solvents / Q000737:chemistry; D013499:Surface Properties; D013816:Thermodynamics; D053782:Transforming Growth Factor beta3 / Q000737:chemistry / Q000378:metabolism; D014867:Water / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000596:Amino Acids; D011506:Proteins; D018125:Receptors, Transforming Growth Factor beta; D012997:Solvents; D053782:Transforming Growth Factor beta3; D014867:Water; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II