title: Prediction of Loops in G Protein-Coupled Receptor Homology Models: Effect of Imprecise Surroundings and Constraints.
abstract: In the present study, we explored the extent to which inaccuracies inherent in homology models of the transmembrane helical cores of G protein-coupled receptors (GPCRs) can impact loop prediction. We demonstrate that loop prediction in homology models is much more difficult than loop reconstruction in crystal structures because of the imprecise positioning of loop anchors. Deriving information from 17 recently available GPCR crystal structures, we estimated all of the possible errors that could occur in loop anchors as the result of comparative modeling. Subsequently, we performed an exhaustive analysis to decipher the effect of these errors on loop modeling using ICM High Precision Sampling. The influence of the presence of other extracellular loops was also explored. Our results reveal that the error space of modeled loop residues is much larger than that of the anchor residues, although modeling a particular extracellular loop in the presence of other extracellular loops provides constraints that help in predicting near-native loop conformations observed in crystal structures. This implies that errors in loop anchor positions introduce increased uncertainty in the modeled loop coordinates. Therefore, for the success of any GPCR structure prediction algorithm, minimizing errors in the helical end points is likely to be critical for successful loop modeling.
authors.affiliation: Department of Chemical Engineering, Indian Institute of Technology Bombay , Mumbai 400076, India.|Department of Pharmacology, Monash University , Clayton, Victoria 3800, Australia.|IITB-Monash Research Academy, IIT Bombay , Mumbai 400076, India.
authors.forename: Bhumika
authors.initials: B
authors.lastname: Arora
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, and Department of Pharmacology, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Coudrat
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, and Department of Pharmacology, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Denise
authors.initials: D
authors.lastname: Wootten
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, and Department of Pharmacology, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
authors.affiliation: Department of Chemical Engineering, Indian Institute of Technology Bombay , Mumbai 400076, India.
authors.forename: Santosh B
authors.initials: SB
authors.lastname: Noronha
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, and Department of Pharmacology, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sexton
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D009010:Monte Carlo Method; D000072756:Protein Conformation, alpha-Helical; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics
chemical_list: D043562:Receptors, G-Protein-Coupled