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Shared Signature Dynamics Tempered by Local Fluctuations Enables Fold Adaptability and Specificity

Recent studies have drawn attention to the evolution of protein dynamics, in addition to sequence and structure, based on the premise structure-encodes-dynamics-encodes-function. Of interest is to understand how functional differentiation is accomplished while maintaining the fold, or how intrinsic...

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Autores principales: Zhang, She, Li, Hongchun, Krieger, James M, Bahar, Ivet
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736388/
https://www.ncbi.nlm.nih.gov/pubmed/31028708
http://dx.doi.org/10.1093/molbev/msz102
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author Zhang, She
Li, Hongchun
Krieger, James M
Bahar, Ivet
author_facet Zhang, She
Li, Hongchun
Krieger, James M
Bahar, Ivet
author_sort Zhang, She
collection PubMed
description Recent studies have drawn attention to the evolution of protein dynamics, in addition to sequence and structure, based on the premise structure-encodes-dynamics-encodes-function. Of interest is to understand how functional differentiation is accomplished while maintaining the fold, or how intrinsic dynamics plays out in the evolution of structural variations and functional specificity. We performed a systematic computational analysis of 26,899 proteins belonging to 116 CATH superfamilies. Characterizing cooperative mechanisms and convergent/divergent features that underlie the shared/differentiated dynamics of family members required a methodology that lends itself to efficient analyses of large ensembles of proteins. We therefore introduced, SignDy, an integrated pipeline for evaluating the signature dynamics of families based on elastic network models. Our analysis confirmed that family members share conserved, highly cooperative (global) modes of motion. Importantly, our analysis discloses a subset of motions that sharply distinguishes subfamilies, which lie in a low-to-intermediate frequency regime of the mode spectrum. This regime has maximal impact on functional differentiation of families into subfamilies, while being evolutionarily conserved among subfamily members. Notably, the high-frequency end of the spectrum also reveals evolutionary conserved features across and within subfamilies; but in sharp contrast to global motions, high-frequency modes are minimally collective. Modulation of robust/conserved global dynamics by low-to-intermediate frequency fluctuations thus emerges as a versatile mechanism ensuring the adaptability of selected folds and the specificity of their subfamilies. SignDy further allows for dynamics-based categorization as a new layer of information relevant to distinctive mechanisms of action of subfamilies, beyond sequence or structural classifications.
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spelling pubmed-67363882019-09-16 Shared Signature Dynamics Tempered by Local Fluctuations Enables Fold Adaptability and Specificity Zhang, She Li, Hongchun Krieger, James M Bahar, Ivet Mol Biol Evol Methods Recent studies have drawn attention to the evolution of protein dynamics, in addition to sequence and structure, based on the premise structure-encodes-dynamics-encodes-function. Of interest is to understand how functional differentiation is accomplished while maintaining the fold, or how intrinsic dynamics plays out in the evolution of structural variations and functional specificity. We performed a systematic computational analysis of 26,899 proteins belonging to 116 CATH superfamilies. Characterizing cooperative mechanisms and convergent/divergent features that underlie the shared/differentiated dynamics of family members required a methodology that lends itself to efficient analyses of large ensembles of proteins. We therefore introduced, SignDy, an integrated pipeline for evaluating the signature dynamics of families based on elastic network models. Our analysis confirmed that family members share conserved, highly cooperative (global) modes of motion. Importantly, our analysis discloses a subset of motions that sharply distinguishes subfamilies, which lie in a low-to-intermediate frequency regime of the mode spectrum. This regime has maximal impact on functional differentiation of families into subfamilies, while being evolutionarily conserved among subfamily members. Notably, the high-frequency end of the spectrum also reveals evolutionary conserved features across and within subfamilies; but in sharp contrast to global motions, high-frequency modes are minimally collective. Modulation of robust/conserved global dynamics by low-to-intermediate frequency fluctuations thus emerges as a versatile mechanism ensuring the adaptability of selected folds and the specificity of their subfamilies. SignDy further allows for dynamics-based categorization as a new layer of information relevant to distinctive mechanisms of action of subfamilies, beyond sequence or structural classifications. Oxford University Press 2019-09 2019-04-27 /pmc/articles/PMC6736388/ /pubmed/31028708 http://dx.doi.org/10.1093/molbev/msz102 Text en © The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Methods
Zhang, She
Li, Hongchun
Krieger, James M
Bahar, Ivet
Shared Signature Dynamics Tempered by Local Fluctuations Enables Fold Adaptability and Specificity
title Shared Signature Dynamics Tempered by Local Fluctuations Enables Fold Adaptability and Specificity
title_full Shared Signature Dynamics Tempered by Local Fluctuations Enables Fold Adaptability and Specificity
title_fullStr Shared Signature Dynamics Tempered by Local Fluctuations Enables Fold Adaptability and Specificity
title_full_unstemmed Shared Signature Dynamics Tempered by Local Fluctuations Enables Fold Adaptability and Specificity
title_short Shared Signature Dynamics Tempered by Local Fluctuations Enables Fold Adaptability and Specificity
title_sort shared signature dynamics tempered by local fluctuations enables fold adaptability and specificity
topic Methods
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736388/
https://www.ncbi.nlm.nih.gov/pubmed/31028708
http://dx.doi.org/10.1093/molbev/msz102
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AT baharivet sharedsignaturedynamicstemperedbylocalfluctuationsenablesfoldadaptabilityandspecificity