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@ARTICLE{Zheng:201205,
      author       = {Zheng, Wenwei and Vargiu, Attlio Vittorio and Rohrdanz,
                      Mary A. and Carloni, Paolo and Clementi, Cecilia},
      title        = {{M}olecular recognition of {DNA} by ligands: {R}oughness
                      and complexity of the free energy profile},
      journal      = {The journal of chemical physics},
      volume       = {139},
      number       = {14},
      issn         = {0021-9606},
      address      = {Melville, NY},
      publisher    = {American Institute of Physics},
      reportid     = {FZJ-2015-03510},
      pages        = {145102 -},
      year         = {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.},
      cin          = {GRS / IAS-5},
      ddc          = {540},
      cid          = {I:(DE-Juel1)GRS-20100316 / I:(DE-Juel1)IAS-5-20120330},
      pnm          = {899 - ohne Topic (POF2-899)},
      pid          = {G:(DE-HGF)POF2-899},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000325780800055},
      pubmed       = {pmid:24116648},
      doi          = {10.1063/1.4824106},
      url          = {https://juser.fz-juelich.de/record/201205},
}