Prediction of loops in G protein-coupled receptor homology models: effect of imprecise surroundings and constraints

Bhumika Arora, Thomas Coudrat, Denise Wootten, Arthur Christopoulos, Santosh B. Noronha, Patrick M. Sexton

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)671-686
Number of pages16
JournalJournal of Chemical Information and Modeling
Volume56
Issue number4
DOIs
Publication statusPublished - 25 Apr 2016

Cite this

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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.",
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Prediction of loops in G protein-coupled receptor homology models : effect of imprecise surroundings and constraints. / Arora, Bhumika; Coudrat, Thomas; Wootten, Denise; Christopoulos, Arthur; Noronha, Santosh B.; Sexton, Patrick M.

In: Journal of Chemical Information and Modeling, Vol. 56, No. 4, 25.04.2016, p. 671-686.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Arora, Bhumika

AU - Coudrat, Thomas

AU - Wootten, Denise

AU - Christopoulos, Arthur

AU - Noronha, Santosh B.

AU - Sexton, Patrick M.

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N2 - 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.

AB - 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.

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