Reliable Generation of Native-Like Decoys Limits Predictive Ability in Fragment-Based Protein Structure Prediction

Our previous work with fragment-assembly methods has demonstrated specific deficiencies in conformational sampling behaviour that, when addressed through improved sampling algorithms, can lead to more reliable prediction of tertiary protein structure when good fragments are available, and when score...

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Autores principales: Kandathil, Shaun M., Garza-Fabre, Mario, Handl, Julia, Lovell, Simon C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843117/
https://www.ncbi.nlm.nih.gov/pubmed/31618996
http://dx.doi.org/10.3390/biom9100612
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author Kandathil, Shaun M.
Garza-Fabre, Mario
Handl, Julia
Lovell, Simon C.
author_facet Kandathil, Shaun M.
Garza-Fabre, Mario
Handl, Julia
Lovell, Simon C.
author_sort Kandathil, Shaun M.
collection PubMed
description Our previous work with fragment-assembly methods has demonstrated specific deficiencies in conformational sampling behaviour that, when addressed through improved sampling algorithms, can lead to more reliable prediction of tertiary protein structure when good fragments are available, and when score values can be relied upon to guide the search to the native basin. In this paper, we present preliminary investigations into two important questions arising from more difficult prediction problems. First, we investigated the extent to which native-like conformational states are generated during multiple runs of our search protocols. We determined that, in cases of difficult prediction, native-like decoys are rarely or never generated. Second, we developed a scheme for decoy retention that balances the objectives of retaining low-scoring structures and retaining conformationally diverse structures sampled during the course of the search. Our method succeeds at retaining more diverse sets of structures, and, for a few targets, more native-like solutions are retained as compared to our original, energy-based retention scheme. However, in general, we found that the rate at which native-like structural states are generated has a much stronger effect on eventual distributions of predictive accuracy in the decoy sets, as compared to the specific decoy retention strategy used. We found that our protocols show differences in their ability to access native-like states for some targets, and this may explain some of the differences in predictive performance seen between these methods. There appears to be an interaction between fragment sets and move operators, which influences the accessibility of native-like structures for given targets. Our results point to clear directions for further improvements in fragment-based methods, which are likely to enable higher accuracy predictions.
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spelling pubmed-68431172019-11-25 Reliable Generation of Native-Like Decoys Limits Predictive Ability in Fragment-Based Protein Structure Prediction Kandathil, Shaun M. Garza-Fabre, Mario Handl, Julia Lovell, Simon C. Biomolecules Article Our previous work with fragment-assembly methods has demonstrated specific deficiencies in conformational sampling behaviour that, when addressed through improved sampling algorithms, can lead to more reliable prediction of tertiary protein structure when good fragments are available, and when score values can be relied upon to guide the search to the native basin. In this paper, we present preliminary investigations into two important questions arising from more difficult prediction problems. First, we investigated the extent to which native-like conformational states are generated during multiple runs of our search protocols. We determined that, in cases of difficult prediction, native-like decoys are rarely or never generated. Second, we developed a scheme for decoy retention that balances the objectives of retaining low-scoring structures and retaining conformationally diverse structures sampled during the course of the search. Our method succeeds at retaining more diverse sets of structures, and, for a few targets, more native-like solutions are retained as compared to our original, energy-based retention scheme. However, in general, we found that the rate at which native-like structural states are generated has a much stronger effect on eventual distributions of predictive accuracy in the decoy sets, as compared to the specific decoy retention strategy used. We found that our protocols show differences in their ability to access native-like states for some targets, and this may explain some of the differences in predictive performance seen between these methods. There appears to be an interaction between fragment sets and move operators, which influences the accessibility of native-like structures for given targets. Our results point to clear directions for further improvements in fragment-based methods, which are likely to enable higher accuracy predictions. MDPI 2019-10-15 /pmc/articles/PMC6843117/ /pubmed/31618996 http://dx.doi.org/10.3390/biom9100612 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kandathil, Shaun M.
Garza-Fabre, Mario
Handl, Julia
Lovell, Simon C.
Reliable Generation of Native-Like Decoys Limits Predictive Ability in Fragment-Based Protein Structure Prediction
title Reliable Generation of Native-Like Decoys Limits Predictive Ability in Fragment-Based Protein Structure Prediction
title_full Reliable Generation of Native-Like Decoys Limits Predictive Ability in Fragment-Based Protein Structure Prediction
title_fullStr Reliable Generation of Native-Like Decoys Limits Predictive Ability in Fragment-Based Protein Structure Prediction
title_full_unstemmed Reliable Generation of Native-Like Decoys Limits Predictive Ability in Fragment-Based Protein Structure Prediction
title_short Reliable Generation of Native-Like Decoys Limits Predictive Ability in Fragment-Based Protein Structure Prediction
title_sort reliable generation of native-like decoys limits predictive ability in fragment-based protein structure prediction
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843117/
https://www.ncbi.nlm.nih.gov/pubmed/31618996
http://dx.doi.org/10.3390/biom9100612
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