Dataset Information

Improving homology modeling from low-sequence identity templates in Rosetta: A case study in GPCRs.

ABSTRACT: As sequencing methodologies continue to advance, the availability of protein sequences far outpaces the ability of structure determination. Homology modeling is used to bridge this gap but relies on high-identity templates for accurate model building. G-protein coupled receptors (GPCRs) represent a significant target class for pharmaceutical therapies in which homology modeling could fill the knowledge gap for structure-based drug design. To date, only about 17% of druggable GPCRs have had their structures characterized at atomic resolution. However, modeling of the remaining 83% is hindered by the low sequence identity between receptors. Here we test key inputs in the model building process using GPCRs as a focus to improve the pipeline in two critical ways: Firstly, we use a blended sequence- and structure-based alignment that accounts for structure conservation in loop regions. Secondly, by merging multiple template structures into one comparative model, the best possible template for every region of a target can be used expanding the conformational space sampled in a meaningful way. This optimization allows for accurate modeling of receptors using templates as low as 20% sequence identity, which accounts for nearly the entire druggable space of GPCRs. A model database of all non-odorant GPCRs is made available at www.rosettagpcr.org. Additionally, all protocols are made available with insights into modifications that may improve accuracy at new targets.

SUBMITTER: Bender BJ

PROVIDER: S-EPMC7652349 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Improving homology modeling from low-sequence identity templates in Rosetta: A case study in GPCRs.

Bender Brian Joseph BJ Marlow Brennica B Meiler Jens J

PLoS computational biology 20201028 10

As sequencing methodologies continue to advance, the availability of protein sequences far outpaces the ability of structure determination. Homology modeling is used to bridge this gap but relies on high-identity templates for accurate model building. G-protein coupled receptors (GPCRs) represent a significant target class for pharmaceutical therapies in which homology modeling could fill the knowledge gap for structure-based drug design. To date, only about 17% of druggable GPCRs have had their ...[more]

PMID: 33112852

Similar Datasets

Project description:MotivationProtein structure prediction has been greatly improved by deep learning, but the contribution of different information is yet to be fully understood. This article studies the impacts of two kinds of information for structure prediction: template and multiple sequence alignment (MSA) embedding. Templates have been used by some methods before, such as AlphaFold2, RoseTTAFold and RaptorX. AlphaFold2 and RosetTTAFold only used templates detected by HHsearch, which may not perform very well on some targets. In addition, sequence embedding generated by pre-trained protein language models has not been fully explored for structure prediction. In this article, we study the impact of templates (including the number of templates, the template quality and how the templates are generated) on protein structure prediction accuracy, especially when the templates are detected by methods other than HHsearch. We also study the impact of sequence embedding (generated by MSATransformer and ESM-1b) on structure prediction.ResultsWe have implemented a deep learning method for protein structure prediction that may take templates and MSA embedding as extra inputs. We study the contribution of templates and MSA embedding to structure prediction accuracy. Our experimental results show that templates can improve structure prediction on 71 of 110 CASP13 (13th Critical Assessment of Structure Prediction) targets and 47 of 91 CASP14 targets, and templates are particularly useful for targets with similar templates. MSA embedding can improve structure prediction on 63 of 91 CASP14 (14th Critical Assessment of Structure Prediction) targets and 87 of 183 CAMEO targets and is particularly useful for proteins with shallow MSAs. When both templates and MSA embedding are used, our method can predict correct folds (TMscore > 0.5) for 16 of 23 CASP14 FM targets and 14 of 18 Continuous Automated Model Evaluation (CAMEO) targets, outperforming RoseTTAFold by 5% and 7%, respectively.Availability and implementationAvailable at https://github.com/xluo233/RaptorXFold.Supplementary informationSupplementary data are available at Bioinformatics online.

Dataset Information

Improving homology modeling from low-sequence identity templates in Rosetta: A case study in GPCRs.

Publications

Improving homology modeling from low-sequence identity templates in Rosetta: A case study in GPCRs.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets