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dc.contributor.author
Gianni, Stefano
dc.contributor.author
Freiberger, Maria Ines
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dc.contributor.author
Jemth, Per
dc.contributor.author
Ferreiro, Diego
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dc.contributor.author
Wolynes, Peter G.
dc.contributor.author
Fuxreiter, Monika
dc.date.available
2022-10-17T17:00:26Z
dc.date.issued
2021-03
dc.identifier.citation
Gianni, Stefano; Freiberger, Maria Ines; Jemth, Per; Ferreiro, Diego; Wolynes, Peter G.; et al.; Fuzziness and Frustration in the Energy Landscape of Protein Folding, Function, and Assembly; American Chemical Society; Accounts of Chemical Research; 54; 5; 3-2021; 1251-1259
dc.identifier.issn
0001-4842
dc.identifier.uri
http://hdl.handle.net/11336/173568
dc.description.abstract
Are all protein interactions fully optimized? Do suboptimal interactions compromise specificity? What is the functional impact of frustration? Why does evolution not optimize some contacts? Proteins and their complexes are best described as ensembles of states populating an energy landscape. These ensembles vary in breadth from narrow ensembles clustered around a single average X-ray structure to broader ensembles encompassing a few different functional “taxonomic” states on to near continua of rapidly interconverting conformations, which are called “fuzzy” or even “intrinsically disordered”. Here we aim to provide a comprehensive framework for confronting the structural and dynamical continuum of protein assemblies by combining the concepts of energetic frustration and interaction fuzziness. The diversity of the protein structural ensemble arises from the frustrated conflicts between the interactions that create the energy landscape. When frustration is minimal after folding, it results in a narrow ensemble, but residual frustrated interactions result in fuzzy ensembles, and this fuzziness allows a versatile repertoire of biological interactions. Here we discuss how fuzziness and frustration play off each other as proteins fold and assemble, viewing their significance from energetic, functional, and evolutionary perspectives. We demonstrate, in particular, that the common physical origin of both concepts is related to the ruggedness of the energy landscapes, intramolecular in the case of frustration and intermolecular in the case of fuzziness. Within this framework, we show that alternative sets of suboptimal contacts may encode specificity without achieving a single structural optimum. Thus, we demonstrate that structured complexes may not be optimized, and energetic frustration is realized via different sets of contacts leading to multiplicity of specific complexes. Furthermore, we propose that these suboptimal, frustrated, or fuzzy interactions are under evolutionary selection and expand the biological repertoire by providing a multiplicity of biological activities. In accord, we show that non-native interactions in folding or interaction landscapes can cooperate to generate diverse functional states, which are essential to facilitate adaptation to different cellular conditions. Thus, we propose that not fully optimized structures may actually be beneficial for biological activities of proteins via an alternative set of suboptimal interactions. The importance of such variability has not been recognized across different areas of biology. This account provides a modern view on folding, function, and assembly across the protein universe. The physical framework presented here is applicable to the structure and dynamics continuum of proteins and opens up new perspectives for drug design involving not fully structured, highly dynamic protein assemblies.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
American Chemical Society
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by/2.5/ar/
dc.subject
fuzzines
dc.subject
frustration
dc.subject
assembly
dc.subject.classification
Biofísica
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dc.subject.classification
Ciencias Biológicas
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dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
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dc.title
Fuzziness and Frustration in the Energy Landscape of Protein Folding, Function, and Assembly
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2022-09-22T00:28:58Z
dc.journal.volume
54
dc.journal.number
5
dc.journal.pagination
1251-1259
dc.journal.pais
Estados Unidos
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dc.description.fil
Fil: Gianni, Stefano. Università degli studi di Roma "La Sapienza"; Italia
dc.description.fil
Fil: Freiberger, Maria Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
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Fil: Jemth, Per. Uppsala Universitet; Suecia
dc.description.fil
Fil: Ferreiro, Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
dc.description.fil
Fil: Wolynes, Peter G.. Rice University; Estados Unidos
dc.description.fil
Fil: Fuxreiter, Monika. Università di Padova; Italia
dc.journal.title
Accounts of Chemical Research
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/acs.accounts.0c00813
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1021/acs.accounts.0c00813
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