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

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dc.citation.articleNumber145102en_US
dc.citation.issueNumber14en_US
dc.citation.journalTitleThe Journal of Chemical Physicsen_US
dc.citation.volumeNumber139en_US
dc.contributor.authorZheng, Wenweien_US
dc.contributor.authorVargiu, Attilio Vittorioen_US
dc.contributor.authorRohrdanz, Mary A.en_US
dc.contributor.authorCarloni, Paoloen_US
dc.contributor.authorClementi, Ceciliaen_US
dc.date.accessioned2017-05-04T18:16:35Zen_US
dc.date.available2017-05-04T18:16:35Zen_US
dc.date.issued2013en_US
dc.description.abstractUnderstanding 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.en_US
dc.identifier.citationZheng, Wenwei, Vargiu, Attilio Vittorio, Rohrdanz, Mary A., et al.. "Molecular recognition of DNA by ligands: Roughness and complexity of the free energy profile." <i>The Journal of Chemical Physics,</i> 139, no. 14 (2013) American Institute of Physics: https://doi.org/10.1063/1.4824106.en_US
dc.identifier.doihttps://doi.org/10.1063/1.4824106en_US
dc.identifier.urihttps://hdl.handle.net/1911/94174en_US
dc.language.isoengen_US
dc.publisherAmerican Institute of Physicsen_US
dc.rightsArticle 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.en_US
dc.titleMolecular recognition of DNA by ligands: Roughness and complexity of the free energy profileen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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