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    Kinetic pathway analysis of an α-helix in two protonation states: Direct observation and optimal dimensionality reduction

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    Issue Date
    2019-02-21
    Author
    Jas, Gouri S.
    Childs, Ed W.
    Kuczera, Krzysztof
    Publisher
    American Institute of Physics
    Type
    Article
    Article Version
    Scholarly/refereed, publisher version
    Rights
    © 2019 Author(s).
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    Abstract
    Thermodynamically stable conformers of secondary structural elements make a stable tertiary/quaternary structure that performs its proper biological function efficiently. Formation mechanisms of secondary and tertiary/quaternary structural elements from the primary structure are driven by the kinetic properties of the respective systems. Here we have carried out thermodynamic and kinetic characterization of an alpha helical heteropeptide in two protonation states, created with the addition and removal of a proton involving a single histidine residue in the primary structure. Applying far-UV circular dichroism spectroscopy, the alpha helix is observed to be significantly more stable in the deprotonated state. Nanosecond laser temperature jump spectroscopy monitoring time-resolved tryptophan fluorescence on the protonated conformer is carried out to measure the kinetics of this system. The measured relaxation rates at a final temperature between 296K and 314 K generated a faster component of 20 ns–11 ns and a slower component of 314 ns–198 ns. Atomically detailed characterization of the helix-coil kinetic pathways is performed based on all-atom molecular dynamics trajectories of the two conformers. Application of clustering and kinetic coarse-graining with optimum dimensionality reduction produced description of the trajectories in terms of kinetic models with two to five states. These models include aggregate states corresponding to helix, coil, and intermediates. The “coil” state involves the largest number of conformations, consistent with the expected high entropy of this structural ensemble. The “helix” aggregate states are found to be mixed with the full helix and partially folded forms. The experimentally observed higher helix stability in the deprotonated form of the alpha helical heteropeptide is reflected in the nature of the “helix” aggregate state arising from the kinetic model. In the protonated form, the “coil” state exhibits the lowest free energy and longest lifetime, while in the deprotonated form, it is the “helix” that is found to be most stable. Overall, the coarse grained models suggest that the protonation of a single histidine residue in the primary structure induces significant changes in the free energy landscape and kinetic network of the studied helix-forming heteropeptide.
    Description
    This article may be downloaded for personal use only. Any other use requires prior permission of the author and AIP Publishing. This article appeared in J. Chem. Phys. 150, 074902 (2019); https://doi.org/10.1063/1.5082192 and may be found at https://aip.scitation.org/doi/full/10.1063/1.5082192
    URI
    http://hdl.handle.net/1808/31441
    DOI
    https://doi.org/10.1063/1.5082192
    Collections
    • Chemistry Scholarly Works [610]
    Citation
    J. Chem. Phys. 150, 074902 (2019); https://doi.org/10.1063/1.5082192

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    785-864-8983

    KU Libraries
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    Lawrence, KS 66045
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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