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    Molecular recognition of DNA by ligands: Roughness and complexity of the free energy profile

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    Author
    Zheng, Wenwei; Vargiu, Attilio Vittorio; Rohrdanz, Mary A.; Carloni, Paolo; Clementi, Cecilia
    Date
    2013
    Abstract
    Understanding the molecular mechanism by which probes and chemotherapeutic agents bind to nucleic acids is a fundamental issue in modern drug design. From a computational perspective, valuable insights are gained by the estimation of free energy landscapes as a function of some collective variables (CVs), which are associated with the molecular recognition event. Unfortunately the choice of CVs is highly non-trivial because of DNA's high flexibility and the presence of multiple association-dissociation events at different locations and/or sliding within the grooves. Here we have applied a modified version of Locally-Scaled Diffusion Map (LSDMap), a nonlinear dimensionality reduction technique for decoupling multiple-timescale dynamics in macromolecular systems, to a metadynamics-based free energy landscape calculated using a set of intuitive CVs. We investigated the binding of the organic drug anthramycin to a DNA 14-mer duplex. By performing an extensive set of metadynamics simulations, we observed sliding of anthramycin along the full-length DNA minor groove, as well as several detachments from multiple sites, including the one identified by X-ray crystallography. As in the case of equilibrium processes, the LSDMap analysis is able to extract the most relevant collective motions, which are associated with the slow processes within the system, i.e., ligand diffusion along the minor groove and dissociation from it. Thus, LSDMap in combination with metadynamics (and possibly every equivalent method) emerges as a powerful method to describe the energetics of ligand binding to DNA without resorting to intuitive ad hoc reaction coordinates.
    Citation
    Zheng, Wenwei, Vargiu, Attilio Vittorio, Rohrdanz, Mary A., et al.. "Molecular recognition of DNA by ligands: Roughness and complexity of the free energy profile." The Journal of Chemical Physics, 139, no. 14 (2013) American Institute of Physics: https://doi.org/10.1063/1.4824106.
    Published Version
    https://doi.org/10.1063/1.4824106
    Type
    Journal article
    Publisher
    American Institute of Physics
    Citable link to this page
    https://hdl.handle.net/1911/94174
    Rights
    Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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    • Chemistry Publications [636]
    • Faculty Publications [4988]

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    Home | FAQ | Contact Us | Privacy Notice | Accessibility Statement
    Managed by the Digital Scholarship Services at Fondren Library, Rice University
    Physical Address: 6100 Main Street, Houston, Texas 77005
    Mailing Address: MS-44, P.O.BOX 1892, Houston, Texas 77251-1892
    Site Map