All-atom molecular dynamics comparison of disease-associated zinc fingers

Academic Article


  • An important regulatory domain of NF- (Formula presented.) B Essential Modulator (NEMO) is a ubiquitin-binding zinc finger, with a tetrahedral CYS3HIS1 zinc-coordinating binding site. Two variations of NEMO’s zinc finger are implicated in various disease states including ectodermal dysplasia and adult-onset glaucoma. To discern structural and dynamical differences between these disease states, we present results of 48- (Formula presented.) s of molecular dynamics simulations for three zinc finger systems each in two states, with and without zinc-bound and correspondingly appropriate cysteine thiol/thiolate configurations. The wild-type protein, often studied for its role in cancer, maintains the most rigid and conformationally stable zinc-bound configuration compared with the diseased counterparts. The glaucoma-related protein has persistent loss of secondary structure except within the dominant conformation. Conformational overlap between wild-type and glaucoma isoforms indicate a competitive binding mechanism may be substantial in the malfunctioning configuration, while the alpha-helical disruption of the ectodermal dysplasia suggests a loss of binding selectivity is responsible for aberrant function.
  • Authors

    Digital Object Identifier (doi)

    Author List

  • Godwin RC; Gmeiner WH; Salsbury FR
  • Start Page

  • 2581
  • End Page

  • 2594
  • Volume

  • 36
  • Issue

  • 10