title: High-energy water sites determine peptide binding affinity and specificity of PDZ domains.
abstract: PDZ domains have well known binding preferences for distinct C-terminal peptide motifs. For most PDZ domains, these motifs are of the form [S/T]-W-[I/L/V]. Although the preference for S/T has been explained by a specific hydrogen bond interaction with a histidine in the PDZ domain and the (I/L/V) is buried in a hydrophobic pocket, the mechanism for Trp specificity at the second to last position has thus far remained unknown. Here, we apply a method to compute the free energies of explicit water molecules and predict that potency gained by Trp binding is due to a favorable release of high-energy water molecules into bulk. The affinities of a series of peptides for both wild-type and mutant forms of the PDZ domain of Erbin correlate very well with the computed free energy of binding of displaced waters, suggesting a direct relationship between water displacement and peptide affinity. Finally, we show a correlation between the magnitude of the displaced water free energy and the degree of Trp-sensitivity among subtypes of the HTRA PDZ family, indicating a water-mediated mechanism for specificity of peptide binding.
authors: Schrödinger Inc., New York, New York 10036, USA. thijs.beuming@schrodinger.com
authors: Thijs
authors: T
authors: Beuming
authors: Ramy
authors: R
authors: Farid
authors: Woody
authors: W
authors: Sherman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry*; D001665:Binding Sites / Q000502:physiology; D003198:Computer Simulation; D006801:Humans; D054731:PDZ Domains / Q000502:physiology*; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding / Q000502:physiology; D014867:Water / Q000737:chemistry*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C413364:ERBIN protein, human; D010455:Peptides; D014867:Water