A generic program for multistate protein design.

Some protein design tasks cannot be modeled by the traditional single state design strategy of finding a sequence that is optimal for a single fixed backbone. Such cases require multistate design, where a single sequence is threaded onto multiple backbones (states) and evaluated for its strengths an...

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Autores principales:	Andrew Leaver-Fay, Ron Jacak, P Benjamin Stranges, Brian Kuhlman
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3e16742d54e546c99b389ddf78928695
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spelling	oai:doaj.org-article:3e16742d54e546c99b389ddf789286952021-11-18T06:50:43ZA generic program for multistate protein design.1932-620310.1371/journal.pone.0020937https://doaj.org/article/3e16742d54e546c99b389ddf789286952011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21754981/?tool=EBIhttps://doaj.org/toc/1932-6203Some protein design tasks cannot be modeled by the traditional single state design strategy of finding a sequence that is optimal for a single fixed backbone. Such cases require multistate design, where a single sequence is threaded onto multiple backbones (states) and evaluated for its strengths and weaknesses on each backbone. For example, to design a protein that can switch between two specific conformations, it is necessary to to find a sequence that is compatible with both backbone conformations. We present in this paper a generic implementation of multistate design that is suited for a wide range of protein design tasks and demonstrate in silico its capabilities at two design tasks: one of redesigning an obligate homodimer into an obligate heterodimer such that the new monomers would not homodimerize, and one of redesigning a promiscuous interface to bind to only a single partner and to no longer bind the rest of its partners. Both tasks contained negative design in that multistate design was asked to find sequences that would produce high energies for several of the states being modeled. Success at negative design was assessed by computationally redocking the undesired protein-pair interactions; we found that multistate design's accuracy improved as the diversity of conformations for the undesired protein-pair interactions increased. The paper concludes with a discussion of the pitfalls of negative design, which has proven considerably more challenging than positive design.Andrew Leaver-FayRon JacakP Benjamin StrangesBrian KuhlmanPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 7, p e20937 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Andrew Leaver-Fay Ron Jacak P Benjamin Stranges Brian Kuhlman A generic program for multistate protein design.
description	Some protein design tasks cannot be modeled by the traditional single state design strategy of finding a sequence that is optimal for a single fixed backbone. Such cases require multistate design, where a single sequence is threaded onto multiple backbones (states) and evaluated for its strengths and weaknesses on each backbone. For example, to design a protein that can switch between two specific conformations, it is necessary to to find a sequence that is compatible with both backbone conformations. We present in this paper a generic implementation of multistate design that is suited for a wide range of protein design tasks and demonstrate in silico its capabilities at two design tasks: one of redesigning an obligate homodimer into an obligate heterodimer such that the new monomers would not homodimerize, and one of redesigning a promiscuous interface to bind to only a single partner and to no longer bind the rest of its partners. Both tasks contained negative design in that multistate design was asked to find sequences that would produce high energies for several of the states being modeled. Success at negative design was assessed by computationally redocking the undesired protein-pair interactions; we found that multistate design's accuracy improved as the diversity of conformations for the undesired protein-pair interactions increased. The paper concludes with a discussion of the pitfalls of negative design, which has proven considerably more challenging than positive design.
format	article
author	Andrew Leaver-Fay Ron Jacak P Benjamin Stranges Brian Kuhlman
author_facet	Andrew Leaver-Fay Ron Jacak P Benjamin Stranges Brian Kuhlman
author_sort	Andrew Leaver-Fay
title	A generic program for multistate protein design.
title_short	A generic program for multistate protein design.
title_full	A generic program for multistate protein design.
title_fullStr	A generic program for multistate protein design.
title_full_unstemmed	A generic program for multistate protein design.
title_sort	generic program for multistate protein design.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/3e16742d54e546c99b389ddf78928695
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A generic program for multistate protein design.

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