title: Contribution of proline to the pre-structuring tendency of transient helical secondary structure elements in intrinsically disordered proteins.
abstract: BACKGROUND
  IDPs function without relying on three-dimensional structures. No clear rationale for such a behavior is available yet. PreSMos are transient secondary structures observed in the target-free IDPs and serve as the target-binding "active" motifs in IDPs. Prolines are frequently found in the flanking regions of PreSMos. Contribution of prolines to the conformational stability of the helical PreSMos in IDPs is investigated.
  
  
  METHODS
  MD simulations are performed for several IDP segments containing a helical PreSMo and the flanking prolines. To measure the influence of flanking-prolines on the structural content of a helical PreSMo calculations were done for wild type as well as for mutant segments with Pro→Asp, His, Lys, or Ala. The change in the helicity due to removal of a proline was measured both for the PreSMo region and for the flanking regions.
  
  
  RESULTS
  The α-helical content in ~70% of the helical PreSMos at the early stage of simulation decreases due to replacement of an N-terminal flanking proline by other residues whereas the helix content in nearly all PreSMos increases when the same replacements occur at the C-terminal flanking region. The helix destabilizing/terminating role of the C-terminal flanking prolines is more pronounced than the helix promoting effect of the N-terminal flanking prolines.
  
  
  CONCLUSIONS
  This work represents a novel example demonstrating that a proline is encoded in an IDP with a defined purpose. The helical PreSMos presage their target-bound conformations. As they most likely mediate IDP-target binding via conformational selection their helical content can be an important feature for IDP function.
authors.affiliation: Division of Convergent Biomedical Research, Biomedical Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 305-806, Republic of Korea.
authors.forename: Chewook
authors.initials: C
authors.lastname: Lee
authors.affiliation: Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, 1518 Budapest, P.O. Box 7, Hungary.
authors.forename: Lajos
authors.initials: L
authors.lastname: Kalmar
authors.affiliation: Department of Molecular Medicine, University of South Florida, Tampa, FL 33612, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Xue
authors.affiliation: Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, 1518 Budapest, P.O. Box 7, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Tompa
authors.affiliation: Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL 33612, USA; Center for Drug Discovery and Innovation, University of South Florida, Tampa, FL 33612, USA.
authors.forename: Gary W
authors.initials: GW
authors.lastname: Daughdrill
authors.affiliation: Department of Molecular Medicine, University of South Florida, Tampa, FL 33612, USA; USF Health Byrd Alzheimer's Research Institute, Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA; Institute for Biological Instrumentation, Russian Academy of Sciences, 142292 Pushchino, Moscow Region, Russia.
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Uversky
authors.affiliation: Division of Convergent Biomedical Research, Biomedical Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 305-806, Republic of Korea; Department of Bioinformatics, University of Science and Technology, 113 Gwahak-ro, Yuseong-gu, Daejeon 305-333, Republic of Korea. Electronic address: khhan600@kribb.re.kr.
authors.forename: Kyou-Hoon
authors.initials: KH
authors.lastname: Han
mesh_terms: D000595:Amino Acid Sequence; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000737:chemistry; D064267:Intrinsically Disordered Proteins / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011392:Proline / Q000737:chemistry*; D017433:Protein Structure, Secondary; D064249:Securin / Q000737:chemistry; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry
chemical_list: D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D064267:Intrinsically Disordered Proteins; D064249:Securin; D016159:Tumor Suppressor Protein p53; D011392:Proline
keywords: Flanking proline; Intrinsically disordered protein (IDP); Molecular dynamics simulation; PreSMo (Pre-Structured Motif)