title: Multi-Component Protein - Protein Docking Based Protocol with External Scoring for Modeling Dimers of G Protein-Coupled Receptors.
abstract: In order to apply structure-based drug design techniques to GPCR complexes, it is essential to model their 3D structure. For this purpose, a multi-component protocol was derived based on protein-protein docking which generates populations of dimers compatible with membrane integration, considering all reasonable interfaces. At the next stage, we applied a scoring procedure based on up to eleven different parameters including shape or electrostatics complementarity. Two methods of consensus scoring were performed: (i) average scores of 100 best scored dimers with respect to each interface, and (ii) frequencies of interfaces among 100 best scored dimers. In general, our multi-component protocol gives correct indications for dimer interfaces that have been observed in X-ray crystal structures of GPCR dimers (opsin dimer, chemokine CXCR4 and CCR5 dimers, κ opioid receptor dimer, β1 adrenergic receptor dimer and smoothened receptor dimer) but also suggests alternative dimerization interfaces. Interestingly, at times these alternative interfaces are scored higher than the experimentally observed ones suggesting them to be also relevant in the life cycle of studied GPCR dimers. Further results indicate that GPCR dimer and higher-order oligomer formation may involve transmembrane helices (TMs) TM1-TM2-TM7, TM3-TM4-TM5 or TM4-TM5-TM6 but not TM1-TM2-TM3 or TM2-TM3-TM4 which is in general agreement with available experimental and computational data.
authors.affiliation: School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, FI-70211 Kuopio, Finland phone: +48815357365; fax: +48815357366. agnieszka.kaczor@umlub.pl.|Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division for Medical Analytics, 4A Chodźki St., PL-20059 Lublin, Poland. agnieszka.kaczor@umlub.pl.|Research Unit on Biomedical Informatics (GRIB), PRBB, Dr Aiguader 88, E-08003 Barcelona, Spain. agnieszka.kaczor@umlub.pl.|Department of Pharmaceutical Chemistry II, Institute of Pharmacy, University of Regensburg, DE-93040 Regensburg, Germany. agnieszka.kaczor@umlub.pl.
authors.forename: Agnieszka A
authors.initials: AA
authors.lastname: Kaczor
authors.affiliation: Research Unit on Biomedical Informatics (GRIB), PRBB, Dr Aiguader 88, E-08003 Barcelona, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Guixà-González
authors.affiliation: Research Unit on Biomedical Informatics (GRIB), PRBB, Dr Aiguader 88, E-08003 Barcelona, Spain.
authors.forename: Pau
authors.initials: P
authors.lastname: Carrió
authors.affiliation: School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, FI-70211 Kuopio, Finland phone: +48815357365; fax: +48815357366.
authors.forename: Antti
authors.initials: A
authors.lastname: Poso
authors.affiliation: Department of Pharmaceutical Chemistry II, Institute of Pharmacy, University of Regensburg, DE-93040 Regensburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Dove
authors.affiliation: Research Unit on Biomedical Informatics (GRIB), PRBB, Dr Aiguader 88, E-08003 Barcelona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Pastor
authors.affiliation: Research Unit on Biomedical Informatics (GRIB), PRBB, Dr Aiguader 88, E-08003 Barcelona, Spain. jana.selent@upf.edu.
authors.forename: Jana
authors.initials: J
authors.lastname: Selent
mesh_terms: D006801:Humans; D062105:Molecular Docking Simulation; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry*
chemical_list: D043562:Receptors, G-Protein-Coupled
keywords: Docking; Protein - protein interactions; Protein modeling