Disentangling direct from indirect co-evolution of residues in protein alignments.

Predicting protein structure from primary sequence is one of the ultimate challenges in computational biology. Given the large amount of available sequence data, the analysis of co-evolution, i.e., statistical dependency, between columns in multiple alignments of protein domain sequences remains one...

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Autores principales:	Lukas Burger, Erik van Nimwegen
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/d444721ac80f405f84279f4fd42201a7
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spelling	oai:doaj.org-article:d444721ac80f405f84279f4fd42201a72021-11-25T05:42:43ZDisentangling direct from indirect co-evolution of residues in protein alignments.1553-734X1553-735810.1371/journal.pcbi.1000633https://doaj.org/article/d444721ac80f405f84279f4fd42201a72010-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20052271/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Predicting protein structure from primary sequence is one of the ultimate challenges in computational biology. Given the large amount of available sequence data, the analysis of co-evolution, i.e., statistical dependency, between columns in multiple alignments of protein domain sequences remains one of the most promising avenues for predicting residues that are contacting in the structure. A key impediment to this approach is that strong statistical dependencies are also observed for many residue pairs that are distal in the structure. Using a comprehensive analysis of protein domains with available three-dimensional structures we show that co-evolving contacts very commonly form chains that percolate through the protein structure, inducing indirect statistical dependencies between many distal pairs of residues. We characterize the distributions of length and spatial distance traveled by these co-evolving contact chains and show that they explain a large fraction of observed statistical dependencies between structurally distal pairs. We adapt a recently developed Bayesian network model into a rigorous procedure for disentangling direct from indirect statistical dependencies, and we demonstrate that this method not only successfully accomplishes this task, but also allows contacts with weak statistical dependency to be detected. To illustrate how additional information can be incorporated into our method, we incorporate a phylogenetic correction, and we develop an informative prior that takes into account that the probability for a pair of residues to contact depends strongly on their primary-sequence distance and the amount of conservation that the corresponding columns in the multiple alignment exhibit. We show that our model including these extensions dramatically improves the accuracy of contact prediction from multiple sequence alignments.Lukas BurgerErik van NimwegenPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 6, Iss 1, p e1000633 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Lukas Burger Erik van Nimwegen Disentangling direct from indirect co-evolution of residues in protein alignments.
description	Predicting protein structure from primary sequence is one of the ultimate challenges in computational biology. Given the large amount of available sequence data, the analysis of co-evolution, i.e., statistical dependency, between columns in multiple alignments of protein domain sequences remains one of the most promising avenues for predicting residues that are contacting in the structure. A key impediment to this approach is that strong statistical dependencies are also observed for many residue pairs that are distal in the structure. Using a comprehensive analysis of protein domains with available three-dimensional structures we show that co-evolving contacts very commonly form chains that percolate through the protein structure, inducing indirect statistical dependencies between many distal pairs of residues. We characterize the distributions of length and spatial distance traveled by these co-evolving contact chains and show that they explain a large fraction of observed statistical dependencies between structurally distal pairs. We adapt a recently developed Bayesian network model into a rigorous procedure for disentangling direct from indirect statistical dependencies, and we demonstrate that this method not only successfully accomplishes this task, but also allows contacts with weak statistical dependency to be detected. To illustrate how additional information can be incorporated into our method, we incorporate a phylogenetic correction, and we develop an informative prior that takes into account that the probability for a pair of residues to contact depends strongly on their primary-sequence distance and the amount of conservation that the corresponding columns in the multiple alignment exhibit. We show that our model including these extensions dramatically improves the accuracy of contact prediction from multiple sequence alignments.
format	article
author	Lukas Burger Erik van Nimwegen
author_facet	Lukas Burger Erik van Nimwegen
author_sort	Lukas Burger
title	Disentangling direct from indirect co-evolution of residues in protein alignments.
title_short	Disentangling direct from indirect co-evolution of residues in protein alignments.
title_full	Disentangling direct from indirect co-evolution of residues in protein alignments.
title_fullStr	Disentangling direct from indirect co-evolution of residues in protein alignments.
title_full_unstemmed	Disentangling direct from indirect co-evolution of residues in protein alignments.
title_sort	disentangling direct from indirect co-evolution of residues in protein alignments.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/d444721ac80f405f84279f4fd42201a7
work_keys_str_mv	AT lukasburger disentanglingdirectfromindirectcoevolutionofresiduesinproteinalignments AT erikvannimwegen disentanglingdirectfromindirectcoevolutionofresiduesinproteinalignments
_version_	1718414546795757568

Disentangling direct from indirect co-evolution of residues in protein alignments.

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