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dc.contributor.author
Di Russo, Natali V.
dc.contributor.author
Marti, Marcelo Adrian
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dc.contributor.author
Roitberg, Adrián
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dc.date.available
2018-12-18T17:26:42Z
dc.date.issued
2014-11
dc.identifier.citation
Di Russo, Natali V.; Marti, Marcelo Adrian; Roitberg, Adrián; Underlying Thermodynamics of pH-Dependent Allostery; American Chemical Society; Journal of Physical Chemistry B; 118; 45; 11-2014; 12818-12826
dc.identifier.issn
1520-6106
dc.identifier.uri
http://hdl.handle.net/11336/66664
dc.description.abstract
Understanding the effects of coupling protein protonation and conformational states is critical to the development of drugs targeting pH sensors and to the rational engineering of pH switches. In this work, we address this issue by performing a comprehensive study of the pH-regulated switch from the closed to the open conformation in nitrophorin 4 (NP4) that determines its pH-dependent activity. Our calculations show that D30 is the only amino acid that has two significantly different pKas in the open and closed conformations, confirming its critical role in regulating pH-dependent behavior. In addition, we describe the free-energy landscape of the conformational change as a function of pH, obtaining accurate estimations of free-energy barriers and equilibrium constants using different methods. The underlying thermodynamic model of the switch workings suggests the possibility of tuning the observed pKa only through the conformational equilibria, keeping the same conformation-specific pKas, as evidenced by the proposed K125L mutant. Moreover, coupling between the protonation and conformational equilibria results in efficient regulation and pH-sensing around physiological pH values only for some combinations of protonation and conformational equilibrium constants, placing constraints on their possible values and leaving a narrow space for protein molecular evolution. The calculations and analysis presented here are of general applicability and provide a guide as to how more complex systems can be studied, offering insight into how pH-regulated allostery works of great value for designing drugs that target pH sensors and for rational engineering of pH switches beyond the common histidine trigger.
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-nc-sa/2.5/ar/
dc.subject
Ph-Dependent
dc.subject
Allostery
dc.subject.classification
Otras Ciencias Químicas
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dc.subject.classification
Ciencias Químicas
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dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
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dc.title
Underlying Thermodynamics of pH-Dependent Allostery
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2018-09-04T19:03:55Z
dc.journal.volume
118
dc.journal.number
45
dc.journal.pagination
12818-12826
dc.journal.pais
Estados Unidos
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dc.journal.ciudad
Washington
dc.description.fil
Fil: Di Russo, Natali V.. University of Florida; Estados Unidos
dc.description.fil
Fil: Marti, Marcelo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina
dc.description.fil
Fil: Roitberg, Adrián. University of Florida; Estados Unidos
dc.journal.title
Journal of Physical Chemistry B
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/abs/10.1021/jp507971v
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/https://dx.doi.org/10.1021/jp507971v
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