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Article: Increased Rigidity of Eglin c at Acidic pH: Evidence from NMR Spin Relaxation and MD Simulations

TitleIncreased Rigidity of Eglin c at Acidic pH: Evidence from NMR Spin Relaxation and MD Simulations
Authors
Issue Date2003
PublisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/biochemistry
Citation
Biochemistry, 2003, v. 42 n. 47, p. 13856-13868 How to Cite?
AbstractTo gain physical insights into how proteins respond to changes in pH, the picosecond to nanosecond time scale dynamics of the small serine protease inhibitor eglin c have been studied by NMR spin relaxation experiments and MD simulations under two pH solution conditions, pH 7 and 3. Like many proteins, eglin c is destabilized by a lowering of the pH, although it retains enough stability to maintain its native conformation at pH 3. Backbone 15N relaxation results show comparable global tumbling times (τm) and model-free order parameters (S2) under the two pH conditions, indicating that the molecule maintains its overall molecular shape and structure at low pH, although the backbone rigidity is slightly increased (〈ΔSpH3-pH7 2〉/〈S2〉 = 0.6%). In contrast, the side-chain methyl dynamics, as measured from 2H relaxation experiments, show a substantial increase in rigidity at lower pH (〈ΔSaxis,pH3-pH7 2/〉/〈 Saxis 2〉 = 14.8%). Molecular dynamics simulations performed at these pH states produce results consistent with NMR measurements, showing that the two methods are in qualitative agreement. Although a full accounting of the physical basis for the concurrent conformational rigidification and destabilization at low pH requires further investigation, the high level of detail in the MD simulations provides a potential molecular mechanism: the breaking of the hydrogen bond between the side chains of Asp46 and Arg53, and changes in electrostatic interactions, appear to allow the binding loop to move closer to the core part of the protein, resulting in a more compact structure at low pH. This more compact structure may be responsible for the increased level of restriction of molecular motion. As these findings show, the stability of a molecular structure is distinct from its conformational rigidity, and the two can even change in opposite directions, against naïve expectation.
Persistent Identifierhttp://hdl.handle.net/10722/167856
ISSN
2015 Impact Factor: 2.876
2015 SCImago Journal Rankings: 1.769
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorHu, Hen_US
dc.contributor.authorClarkson, MWen_US
dc.contributor.authorHermans, Jen_US
dc.contributor.authorLee, ALen_US
dc.date.accessioned2012-10-08T03:12:15Z-
dc.date.available2012-10-08T03:12:15Z-
dc.date.issued2003en_US
dc.identifier.citationBiochemistry, 2003, v. 42 n. 47, p. 13856-13868en_US
dc.identifier.issn0006-2960en_US
dc.identifier.urihttp://hdl.handle.net/10722/167856-
dc.description.abstractTo gain physical insights into how proteins respond to changes in pH, the picosecond to nanosecond time scale dynamics of the small serine protease inhibitor eglin c have been studied by NMR spin relaxation experiments and MD simulations under two pH solution conditions, pH 7 and 3. Like many proteins, eglin c is destabilized by a lowering of the pH, although it retains enough stability to maintain its native conformation at pH 3. Backbone 15N relaxation results show comparable global tumbling times (τm) and model-free order parameters (S2) under the two pH conditions, indicating that the molecule maintains its overall molecular shape and structure at low pH, although the backbone rigidity is slightly increased (〈ΔSpH3-pH7 2〉/〈S2〉 = 0.6%). In contrast, the side-chain methyl dynamics, as measured from 2H relaxation experiments, show a substantial increase in rigidity at lower pH (〈ΔSaxis,pH3-pH7 2/〉/〈 Saxis 2〉 = 14.8%). Molecular dynamics simulations performed at these pH states produce results consistent with NMR measurements, showing that the two methods are in qualitative agreement. Although a full accounting of the physical basis for the concurrent conformational rigidification and destabilization at low pH requires further investigation, the high level of detail in the MD simulations provides a potential molecular mechanism: the breaking of the hydrogen bond between the side chains of Asp46 and Arg53, and changes in electrostatic interactions, appear to allow the binding loop to move closer to the core part of the protein, resulting in a more compact structure at low pH. This more compact structure may be responsible for the increased level of restriction of molecular motion. As these findings show, the stability of a molecular structure is distinct from its conformational rigidity, and the two can even change in opposite directions, against naïve expectation.en_US
dc.languageengen_US
dc.publisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/biochemistryen_US
dc.relation.ispartofBiochemistryen_US
dc.subject.meshAnimalsen_US
dc.subject.meshComputer Simulationen_US
dc.subject.meshEntropyen_US
dc.subject.meshHydrogen-Ion Concentrationen_US
dc.subject.meshLeechesen_US
dc.subject.meshModels, Molecularen_US
dc.subject.meshNuclear Magnetic Resonance, Biomolecular - Methodsen_US
dc.subject.meshProtein Conformationen_US
dc.subject.meshProtein Foldingen_US
dc.subject.meshProteinsen_US
dc.subject.meshProtonsen_US
dc.subject.meshSerpins - Chemistryen_US
dc.subject.meshSolutionsen_US
dc.subject.meshStatic Electricityen_US
dc.subject.meshThermodynamicsen_US
dc.titleIncreased Rigidity of Eglin c at Acidic pH: Evidence from NMR Spin Relaxation and MD Simulationsen_US
dc.typeArticleen_US
dc.identifier.emailHu, H:haohu@hku.hken_US
dc.identifier.authorityHu, H=rp00707en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1021/bi035015zen_US
dc.identifier.pmid14636053-
dc.identifier.scopuseid_2-s2.0-0345707599en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0345707599&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume42en_US
dc.identifier.issue47en_US
dc.identifier.spage13856en_US
dc.identifier.epage13868en_US
dc.identifier.isiWOS:000186846800009-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridHu, H=7404097564en_US
dc.identifier.scopusauthoridClarkson, MW=8147269900en_US
dc.identifier.scopusauthoridHermans, J=7201896483en_US
dc.identifier.scopusauthoridLee, AL=7405629964en_US
dc.identifier.citeulike960430-

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