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Defining a length scale for millisecond-timescale protein conformational exchange

Although atomic resolution 3D structures of protein native states and some folding intermediates are available, the mechanism of interconversion between such states remains poorly understood. Here we study the four-helix bundle FF module, which folds via a transiently formed and sparsely populated c... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America Jul 9, 2013, Vol.110(28), p.11391
Main Author: Sekhar, Ashok
Other Authors: Vallurupalli, Pramodh , Kay, Lewis
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 00278424 ; E-ISSN: 10916490
Link: http://search.proquest.com/docview/1401944531/?pq-origsite=primo
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title: Defining a length scale for millisecond-timescale protein conformational exchange
format: Article
creator:
  • Sekhar, Ashok
  • Vallurupalli, Pramodh
  • Kay, Lewis
subjects:
  • Fluid Mechanics
  • Amino Acids
  • Nuclear Magnetic Resonance–NMR
  • Hydrogen Bonds
  • Protein Folding
  • Solvents
ispartof: Proceedings of the National Academy of Sciences of the United States of America, Jul 9, 2013, Vol.110(28), p.11391
description: Although atomic resolution 3D structures of protein native states and some folding intermediates are available, the mechanism of interconversion between such states remains poorly understood. Here we study the four-helix bundle FF module, which folds via a transiently formed and sparsely populated compact on-pathway intermediate, I. Relaxation dispersion NMR spectroscopy has previously been used to elucidate the 3D structure of this intermediate and to establish that the conformational exchange between the I and the native, N, states of the FF domain is driven predominantly by water dynamics. In the present study we use NMR methods to define a length scale for the FF I-N transition, namely the effective hydrodynamic radius (EHR) that provides an average measure of the size of the structural units participating in the transition at any given time. Our experiments establish that the EHR is less than 4 A, on the order of the size of one to two amino acid side chains, much smaller than the FF domain hydrodynamic radius (13 A). The small magnitude of the EHR provides strong evidence that the I-N interconversion does not proceed via the synchronous motion of large clusters of amino acid residues, but rather by the exposure/burial of one or two side chains from solvent at any given time. Because the hydration of small hydrophobic solutes (< 4 A) does not involve considerable dewetting or disruption of the water-hydrogen bonding network, the FF domain I-N transition does not require appreciable changes to the structure of the surrounding water. [PUBLICATION ]
language: eng
source:
identifier: ISSN: 00278424 ; E-ISSN: 10916490
fulltext: fulltext
issn:
  • 00278424
  • 0027-8424
  • 10916490
  • 1091-6490
url: Link


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titleDefining a length scale for millisecond-timescale protein conformational exchange
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ispartofProceedings of the National Academy of Sciences of the United States of America, Jul 9, 2013, Vol.110(28), p.11391
identifierISSN: 00278424 ; E-ISSN: 10916490
subjectFluid Mechanics ; Amino Acids ; Nuclear Magnetic Resonance–NMR ; Hydrogen Bonds ; Protein Folding ; Solvents
descriptionAlthough atomic resolution 3D structures of protein native states and some folding intermediates are available, the mechanism of interconversion between such states remains poorly understood. Here we study the four-helix bundle FF module, which folds via a transiently formed and sparsely populated compact on-pathway intermediate, I. Relaxation dispersion NMR spectroscopy has previously been used to elucidate the 3D structure of this intermediate and to establish that the conformational exchange between the I and the native, N, states of the FF domain is driven predominantly by water dynamics. In the present study we use NMR methods to define a length scale for the FF I-N transition, namely the effective hydrodynamic radius (EHR) that provides an average measure of the size of the structural units participating in the transition at any given time. Our experiments establish that the EHR is less than 4 A, on the order of the size of one to two amino acid side chains, much smaller than the FF domain hydrodynamic radius (13 A). The small magnitude of the EHR provides strong evidence that the I-N interconversion does not proceed via the synchronous motion of large clusters of amino acid residues, but rather by the exposure/burial of one or two side chains from solvent at any given time. Because the hydration of small hydrophobic solutes (< 4 A) does not involve considerable dewetting or disruption of the water-hydrogen bonding network, the FF domain I-N transition does not require appreciable changes to the structure of the surrounding water. [PUBLICATION ]
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abstractAlthough atomic resolution 3D structures of protein native states and some folding intermediates are available, the mechanism of interconversion between such states remains poorly understood. Here we study the four-helix bundle FF module, which folds via a transiently formed and sparsely populated compact on-pathway intermediate, I. Relaxation dispersion NMR spectroscopy has previously been used to elucidate the 3D structure of this intermediate and to establish that the conformational exchange between the I and the native, N, states of the FF domain is driven predominantly by water dynamics. In the present study we use NMR methods to define a length scale for the FF I-N transition, namely the effective hydrodynamic radius (EHR) that provides an average measure of the size of the structural units participating in the transition at any given time. Our experiments establish that the EHR is less than 4 A, on the order of the size of one to two amino acid side chains, much smaller than the FF domain hydrodynamic radius (13 A). The small magnitude of the EHR provides strong evidence that the I-N interconversion does not proceed via the synchronous motion of large clusters of amino acid residues, but rather by the exposure/burial of one or two side chains from solvent at any given time. Because the hydration of small hydrophobic solutes (< 4 A) does not involve considerable dewetting or disruption of the water-hydrogen bonding network, the FF domain I-N transition does not require appreciable changes to the structure of the surrounding water. [PUBLICATION ABSTRACT]
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