Molecular dynamics simulation of the SH3 domain aggregation suggests a generic amyloidogenesis mechanism

J Mol Biol. 2002 Dec 6;324(4):851-7. doi: 10.1016/s0022-2836(02)01112-9.

Abstract

We use molecular dynamics simulation to study the aggregation of Src SH3 domain proteins. For the case of two proteins, we observe two possible aggregation conformations: the closed form dimer and the open aggregation state. The closed dimer is formed by "domain swapping"-the two proteins exchange their RT-loops. All the hydrophobic residues are buried inside the dimer so proteins cannot further aggregate into elongated amyloid fibrils. We find that the open structure-stabilized by backbone hydrogen bond interactions-packs the RT-loops together by swapping the two strands of the RT-loop. The packed RT-loops form a beta-sheet structure and expose the backbone to promote further aggregation. We also simulate more than two proteins, and find that the aggregate adopts a fibrillar double beta-sheet structure, which is formed by packing the RT-loops from different proteins. Our simulations are consistent with a possible generic amyloidogenesis scenario.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Amyloid / chemistry
  • Amyloid / metabolism
  • Amyloidosis / etiology
  • Computer Simulation
  • Crystallography, X-Ray
  • Dimerization
  • Hydrogen Bonding
  • Models, Molecular
  • Peptide Fragments / chemistry
  • Protein Conformation
  • Protein Folding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Protein Subunits / chemistry
  • Sequence Alignment
  • Temperature
  • src Homology Domains*

Substances

  • Amyloid
  • Peptide Fragments
  • Protein Subunits

Associated data

  • PDB/1NLO