Probing Hydration Patterns in Class-A GPCRs via Biased MD: The A2A Receptor

J Chem Theory Comput. 2016 Dec 13;12(12):6049-6061. doi: 10.1021/acs.jctc.6b00475. Epub 2016 Nov 10.

Abstract

Herein, we present a new computational approach for analyzing hydration patterns in biomolecular systems. This protocol aims to efficiently identify regions where structural waters may be located and, in the case of protein-ligand binding, where displacing one or more water molecules could be advantageous in terms of affinity and/or residence time. We validated our approach on the adenosine A2A receptor, a target of significant pharmaceutical relevance. The results of the approach are enriched with an extensive analysis of hydration in A2A and other members of the A-family of GPCRs using available crystallographic evidence and reviewing existing literature. As per the protein-ligand complex case, we conducted a more detailed study of a series of triazine analogues inhibiting A2A. The proposed approach provides results in good agreement with existing data and offers interpretability and simple and fast applicability.

MeSH terms

  • Ligands
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptor, Adenosine A2A / chemistry*
  • Receptor, Adenosine A2A / metabolism
  • Thermodynamics
  • Triazines / chemistry
  • Triazines / metabolism
  • Water / chemistry

Substances

  • Ligands
  • Receptor, Adenosine A2A
  • Triazines
  • Water