HomolWat: a web server tool to incorporate 'homologous' water molecules into GPCR structures.

Adrián García-Recio,Arnau Cordomí,Eduardo Mayol,Johanna K S Tiemann,Mireia Olivella,Peter W Hildebrand,Ramon Guixà-González

doi:10.1093/nar/gkaa440

Abstract

Internal water molecules play an essential role in the structure and function of membrane proteins including G protein-coupled receptors (GPCRs). However, technical limitations severely influence the number and certainty of observed water molecules in 3D structures. This may compromise the accuracy of further structural studies such as docking calculations or molecular dynamics simulations. Here we present HomolWat, a web application for incorporating water molecules into GPCR structures by using template-based modelling of homologous water molecules obtained from high-resolution structures. While there are various tools available to predict the positions of internal waters using energy-based methods, the approach of borrowing lacking water molecules from homologous GPCR structures makes HomolWat unique. The tool can incorporate water molecules into a protein structure in about a minute with around 85% of water recovery. The web server is freely available at http://lmc.uab.es/homolwat.

Highlights

Water molecules confined inside cavities in a protein, named ordered or internal water molecules, play an essential role in the structure and function of proteins, ligand binding mechanisms, and catalytic reactions
The input of HomolWat is a file with the 3D structure in the PDB format whereas the output is the same structure containing homologous internal water molecules obtained from the HomolWat reference database
The overall HomolWat protocol for water molecule placement contains steps as follows: First, HomolWat uses Blast+ to perform a multiple sequence alignment of the input structure sequence against all G protein-coupled receptors (GPCRs) sequences from receptors hosted in HomolWatDB, resulting in a list of homologous structures with water molecules sorted according to their Blast+ score

Summary

Introduction

Water molecules confined inside cavities in a protein, named ordered or internal water molecules, play an essential role in the structure and function of proteins, ligand binding mechanisms, and catalytic reactions. Despite sharing a common seven ␣helical transmembrane architecture and similar conformation changes upon activation [1,6], they recognize a wide diversity of extracellular signals like hormones, neurotransmitters or entire proteins. As a result, they play a key role in signal transduction and have become targets of 35% of the currently approved drugs [7]. Molecular dynamics simulations have shown that internal water molecules are highly conserved among GPCRs and participate in their common activation mechanism [9] Overall, this emphasizes the important role that water molecules play in GPCR function

Methods

Results

Conclusion