CATS (Coordinates of Atoms by Taylor Series): protein design with backbone flexibility in all locally feasible directions

MOTIVATION: When proteins mutate or bind to ligands, their backbones often move significantly, especially in loop regions. Computational protein design algorithms must model these motions in order to accurately optimize protein stability and binding affinity. However, methods for backbone conformati...

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Autores principales: Hallen, Mark A, Donald, Bruce R
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870559/
https://www.ncbi.nlm.nih.gov/pubmed/28882005
http://dx.doi.org/10.1093/bioinformatics/btx277
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author Hallen, Mark A
Donald, Bruce R
author_facet Hallen, Mark A
Donald, Bruce R
author_sort Hallen, Mark A
collection PubMed
description MOTIVATION: When proteins mutate or bind to ligands, their backbones often move significantly, especially in loop regions. Computational protein design algorithms must model these motions in order to accurately optimize protein stability and binding affinity. However, methods for backbone conformational search in design have been much more limited than for sidechain conformational search. This is especially true for combinatorial protein design algorithms, which aim to search a large sequence space efficiently and thus cannot rely on temporal simulation of each candidate sequence. RESULTS: We alleviate this difficulty with a new parameterization of backbone conformational space, which represents all degrees of freedom of a specified segment of protein chain that maintain valid bonding geometry (by maintaining the original bond lengths and angles and ω dihedrals). In order to search this space, we present an efficient algorithm, CATS, for computing atomic coordinates as a function of our new continuous backbone internal coordinates. CATS generalizes the iMinDEE and EPIC protein design algorithms, which model continuous flexibility in sidechain dihedrals, to model continuous, appropriately localized flexibility in the backbone dihedrals [Formula: see text] and ψ as well. We show using 81 test cases based on 29 different protein structures that CATS finds sequences and conformations that are significantly lower in energy than methods with less or no backbone flexibility do. In particular, we show that CATS can model the viability of an antibody mutation known experimentally to increase affinity, but that appears sterically infeasible when modeled with less or no backbone flexibility. AVAILABILITY AND IMPLEMENTATION: Our code is available as free software at https://github.com/donaldlab/OSPREY_refactor. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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spelling pubmed-58705592018-04-05 CATS (Coordinates of Atoms by Taylor Series): protein design with backbone flexibility in all locally feasible directions Hallen, Mark A Donald, Bruce R Bioinformatics Ismb/Eccb 2017: The 25th Annual Conference Intelligent Systems for Molecular Biology Held Jointly with the 16th Annual European Conference on Computational Biology, Prague, Czech Republic, July 21–25, 2017 MOTIVATION: When proteins mutate or bind to ligands, their backbones often move significantly, especially in loop regions. Computational protein design algorithms must model these motions in order to accurately optimize protein stability and binding affinity. However, methods for backbone conformational search in design have been much more limited than for sidechain conformational search. This is especially true for combinatorial protein design algorithms, which aim to search a large sequence space efficiently and thus cannot rely on temporal simulation of each candidate sequence. RESULTS: We alleviate this difficulty with a new parameterization of backbone conformational space, which represents all degrees of freedom of a specified segment of protein chain that maintain valid bonding geometry (by maintaining the original bond lengths and angles and ω dihedrals). In order to search this space, we present an efficient algorithm, CATS, for computing atomic coordinates as a function of our new continuous backbone internal coordinates. CATS generalizes the iMinDEE and EPIC protein design algorithms, which model continuous flexibility in sidechain dihedrals, to model continuous, appropriately localized flexibility in the backbone dihedrals [Formula: see text] and ψ as well. We show using 81 test cases based on 29 different protein structures that CATS finds sequences and conformations that are significantly lower in energy than methods with less or no backbone flexibility do. In particular, we show that CATS can model the viability of an antibody mutation known experimentally to increase affinity, but that appears sterically infeasible when modeled with less or no backbone flexibility. AVAILABILITY AND IMPLEMENTATION: Our code is available as free software at https://github.com/donaldlab/OSPREY_refactor. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. Oxford University Press 2017-07-15 2017-07-12 /pmc/articles/PMC5870559/ /pubmed/28882005 http://dx.doi.org/10.1093/bioinformatics/btx277 Text en © The Author 2017. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Ismb/Eccb 2017: The 25th Annual Conference Intelligent Systems for Molecular Biology Held Jointly with the 16th Annual European Conference on Computational Biology, Prague, Czech Republic, July 21–25, 2017
Hallen, Mark A
Donald, Bruce R
CATS (Coordinates of Atoms by Taylor Series): protein design with backbone flexibility in all locally feasible directions
title CATS (Coordinates of Atoms by Taylor Series): protein design with backbone flexibility in all locally feasible directions
title_full CATS (Coordinates of Atoms by Taylor Series): protein design with backbone flexibility in all locally feasible directions
title_fullStr CATS (Coordinates of Atoms by Taylor Series): protein design with backbone flexibility in all locally feasible directions
title_full_unstemmed CATS (Coordinates of Atoms by Taylor Series): protein design with backbone flexibility in all locally feasible directions
title_short CATS (Coordinates of Atoms by Taylor Series): protein design with backbone flexibility in all locally feasible directions
title_sort cats (coordinates of atoms by taylor series): protein design with backbone flexibility in all locally feasible directions
topic Ismb/Eccb 2017: The 25th Annual Conference Intelligent Systems for Molecular Biology Held Jointly with the 16th Annual European Conference on Computational Biology, Prague, Czech Republic, July 21–25, 2017
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870559/
https://www.ncbi.nlm.nih.gov/pubmed/28882005
http://dx.doi.org/10.1093/bioinformatics/btx277
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