High‐energy water sites determine peptide binding affinity and specificity of PDZ domains

• Published in: Protein science Vol. 18; no. 8; pp. 1609 - 1619
• Main Authors: Beuming, Thijs, Farid, Ramy, Sherman, Woody
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.08.2009
• Subjects: Adaptor Proteins, Signal Transducing - chemistry; Binding Sites - physiology; Computer Simulation; Humans; molecular dynamics; PDZ domain; PDZ Domains - physiology; peptide binding affinity; Peptides - chemistry; Protein Binding - physiology; Water - chemistry; water thermodynamics; WaterMap
• ISSN: 0961-8368; 1469-896X
• DOI: 10.1002/pro.177

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.