Water Networks as Hydrophobic Recognition Motifs in Proteins
Abstract
Abstract The hydrophobic effect is a central force in molecular recognition, typically attributed to the ordering of water molecules around apolar groups. Hydrophobic interaction sites on proteins are therefore readily predicted based on surface polarity. Yet, in the bromodomain‐containing protein 4 (BRD4), a well‐known hydrophobic hot spot is paradoxically lined by a network of water molecules. Here we combine binding assays, structural data, molecular dynamics, and free‐energy calculations to resolve this apparent contradiction. We show that the water network functions as a hydrophobic recognition motif that cannot accommodate polar groups without disruption. Instead, as the protein pre‐organizes the water network, apolar groups can bind with minimal entropic cost. In turn, they reinforce the surrounding hydrogen‐bond network, limiting the mobility of the entire protein–water assembly. With this perspective, we identify water networks potentially functioning as hydrophobic motifs in other pharmacological targets, revealing a general but overlooked recognition element with broad implications in drug discovery and protein design.
Article Details
Authors (13)
Serena G. Piticchio
Departament de Farmacia i Tecnología Farmacèutica, i Fisicoquímica Institut de Biomedicina (IBUB), Universitat de Barcelona Av. Joan XXIII, 27‐31, E‐08028 Barcelona Spain
Miriam Martínez‐Cartró
Departament de Farmacia i Tecnología Farmacèutica, i Fisicoquímica Institut de Biomedicina (IBUB), Universitat de Barcelona Av. Joan XXIII, 27‐31, E‐08028 Barcelona Spain
Salvatore Scaffidi
Departament de Farmacia i Tecnología Farmacèutica, i Fisicoquímica Institut de Biomedicina (IBUB), Universitat de Barcelona Av. Joan XXIII, 27‐31, E‐08028 Barcelona Spain
Sergio Rodríguez‐Arévalo
Laboratory of Medicinal Chemistry Department of Pharmacology, Toxicology and Medicinal Chemistry Faculty of Pharmacy and Food Sciences and Institute of Biomedicine (IBUB) University of Barcelona Av. Joan XXIII, 27‐31, E‐08028 Barcelona Spain
Andrea Bagán
Laboratory of Medicinal Chemistry Department of Pharmacology, Toxicology and Medicinal Chemistry Faculty of Pharmacy and Food Sciences and Institute of Biomedicine (IBUB) University of Barcelona Av. Joan XXIII, 27‐31, E‐08028 Barcelona Spain
Ainoa Sánchez‐Arfelis
Laboratory of Medicinal Chemistry Department of Pharmacology, Toxicology and Medicinal Chemistry Faculty of Pharmacy and Food Sciences and Institute of Biomedicine (IBUB) University of Barcelona Av. Joan XXIII, 27‐31, E‐08028 Barcelona Spain
Sarah Picaud
Nuffield Department of Medicine, Oxford University Old Road Campus Research Building Oxford OX2 7DQ UK
Tobias Krojer
Structural Genomics Consortium, Nuffield Department of Medicine Oxford University, Old Road Campus Research Building Roosevelt Drive Oxford OX3 7DQ UK
Panagis Filippakopoulos
Nuffield Department of Medicine, Oxford University Old Road Campus Research Building Oxford OX2 7DQ UK
Frank von Delft
Carmen Escolano
Laboratory of Medicinal Chemistry Department of Pharmacology, Toxicology and Medicinal Chemistry Faculty of Pharmacy and Food Sciences and Institute of Biomedicine (IBUB) University of Barcelona Av. Joan XXIII, 27‐31, E‐08028 Barcelona Spain
Carles Galdeano
Departament de Farmacia i Tecnología Farmacèutica, i Fisicoquímica Institut de Biomedicina (IBUB), Universitat de Barcelona Av. Joan XXIII, 27‐31, E‐08028 Barcelona Spain
Xavier Barril
Departament de Farmacia i Tecnología Farmacèutica, i Fisicoquímica Institut de Biomedicina (IBUB), Universitat de Barcelona Av. Joan XXIII, 27‐31, E‐08028 Barcelona Spain