title: An Ensemble-Based Protocol for the Computational Prediction of Helix-Helix Interactions in G Protein-Coupled Receptors using Coarse-Grained Molecular Dynamics.
abstract: The accurate identification of the specific points of interaction between G protein-coupled receptor (GPCR) oligomers is essential for the design of receptor ligands targeting oligomeric receptor targets. A coarse-grained molecular dynamics computer simulation approach would provide a compelling means of identifying these specific protein-protein interactions and could be applied both for known oligomers of interest and as a high-throughput screen to identify novel oligomeric targets. However, to be effective, this in silico modeling must provide accurate, precise, and reproducible information. This has been achieved recently in numerous biological systems using an ensemble-based all-atom molecular dynamics approach. In this study, we describe an equivalent methodology for ensemble-based coarse-grained simulations. We report the performance of this method when applied to four different GPCRs known to oligomerize using error analysis to determine the ensemble size and individual replica simulation time required. Our measurements of distance between residues shown to be involved in oligomerization of the fifth transmembrane domain from the adenosine A2Areceptor are in very good agreement with the existing biophysical data and provide information about the nature of the contact interface that cannot be determined experimentally. Calculations of distance between rhodopsin, CXCR4, and β1AR transmembrane domains reported to form contact points in homodimers correlate well with the corresponding measurements obtained from experimental structural data, providing an ability to predict contact interfaces computationally. Interestingly, error analysis enables identification of noninteracting regions. Our results confirm that GPCR interactions can be reliably predicted using this novel methodology.
authors.affiliation: Institute of Structural and Molecular Biology, Research Department of Structural and Molecular Biology, Division of Biosciences, University College London , London, WC1E 6BT, United Kingdom.|King Saud University , Riyadh, Kingdom of Saudi Arabia.
authors.forename: Nojood A
authors.initials: NA
authors.lastname: Altwaijry
authors.affiliation: Institute of Structural and Molecular Biology, Research Department of Structural and Molecular Biology, Division of Biosciences, University College London , London, WC1E 6BT, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Baron
authors.affiliation: Centre for Computational Science, Department of Chemistry, University College London , London WC1H 0AJ, United Kingdom.
authors.forename: David W
authors.identifier: http://orcid.org/0000-0002-5124-8044
authors.initials: DW
authors.lastname: Wright
authors.affiliation: Centre for Computational Science, Department of Chemistry, University College London , London WC1H 0AJ, United Kingdom.
authors.forename: Peter V
authors.identifier: http://orcid.org/0000-0002-8787-7256
authors.initials: PV
authors.lastname: Coveney
authors.affiliation: Institute of Structural and Molecular Biology, Research Department of Structural and Molecular Biology, Division of Biosciences, University College London , London, WC1E 6BT, United Kingdom.
authors.forename: Andrea
authors.identifier: http://orcid.org/0000-0002-7250-2208
authors.initials: A
authors.lastname: Townsend-Nicholson
mesh_terms: D000595:Amino Acid Sequence; D030562:Databases, Protein; D006801:Humans; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072417:Protein Domains; D055503:Protein Multimerization; D011941:Receptors, Adrenergic / Q000737:chemistry; D019718:Receptors, CXCR4 / Q000737:chemistry; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry*; D012243:Rhodopsin / Q000737:chemistry
chemical_list: D011941:Receptors, Adrenergic; D019718:Receptors, CXCR4; D043562:Receptors, G-Protein-Coupled; D012243:Rhodopsin