Molecular simulations of the fluctuating conformational dynamics of intrinsically disordered proteins

Phys Rev E Stat Nonlin Soft Matter Phys. 2012 Oct;86(4 Pt 1):041910. doi: 10.1103/PhysRevE.86.041910. Epub 2012 Oct 12.

Abstract

Intrinsically disordered proteins (IDPs) do not possess well-defined three-dimensional structures in solution under physiological conditions. We develop all-atom, united-atom, and coarse-grained Langevin dynamics simulations for the IDP α-synuclein that include geometric, attractive hydrophobic, and screened electrostatic interactions and are calibrated to the inter-residue separations measured in recent single-molecule fluorescence energy transfer (smFRET) experiments. We find that α-synuclein is disordered, with conformational statistics that are intermediate between random walk and collapsed globule behavior. An advantage of calibrated molecular simulations over constraint methods is that physical forces act on all residues, not only on residue pairs that are monitored experimentally, and these simulations can be used to study oligomerization and aggregation of multiple α-synuclein proteins that may precede amyloid formation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Amyloid / chemistry*
  • Biophysics / methods*
  • Calibration
  • Fluorescence Resonance Energy Transfer / methods
  • Humans
  • Hydrogen-Ion Concentration
  • Hydrophobic and Hydrophilic Interactions
  • Models, Molecular
  • Models, Statistical
  • Molecular Conformation*
  • Molecular Sequence Data
  • Monte Carlo Method
  • Parkinson Disease / metabolism
  • Protein Conformation
  • Protein Structure, Secondary
  • Proteins / chemistry*
  • Solvents / chemistry
  • alpha-Synuclein / chemistry*

Substances

  • Amyloid
  • Proteins
  • Solvents
  • alpha-Synuclein