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dc.contributor.authorZheng, Wenwei
Vargiu, Attilio Vittorio
Rohrdanz, Mary A.
Carloni, Paolo
Clementi, Cecilia
dc.date.accessioned 2017-05-04T18:16:35Z
dc.date.available 2017-05-04T18:16:35Z
dc.date.issued 2013
dc.identifier.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.
dc.identifier.urihttps://hdl.handle.net/1911/94174
dc.description.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.
dc.language.iso eng
dc.publisher American Institute of Physics
dc.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.
dc.title Molecular recognition of DNA by ligands: Roughness and complexity of the free energy profile
dc.type Journal article
dc.citation.journalTitle The Journal of Chemical Physics
dc.citation.volumeNumber 139
dc.citation.issueNumber 14
dc.type.dcmi Text
dc.identifier.doihttps://doi.org/10.1063/1.4824106
dc.identifier.pmcid PMC3808439
dc.type.publication publisher version
dc.citation.articleNumber 145102


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