NR ANUL
AU Gsponer,J.; Haberthur,U.; Caflisch,A.
TI The role of side-chain interactions in the early steps of aggregation: Molecular dynamics simulations of an amyloid-forming peptide from the yeast prion Sup35.
QU Proceedings of the National Academy of Sciences of the United States of America 2003 Apr 29; 100(9): 5154-9
PT journal article
AB Understanding the early steps of aggregation at atomic detail might be crucial for the rational design of therapeutics preventing diseases associated with amyloid deposits. In this paper, aggregation of the heptapeptide GNNQQNY, from the N-terminal prion-determining domain of the yeast protein Sup35, was studied by 20 molecular dynamics runs for a total simulation time of 20 micros. The simulations generate in-register parallel packing of GNNQQNY beta-strands that is consistent with x-ray diffraction and Fourier transform infrared data. The statistically preferred aggregation pathway does not correspond to a purely downhill profile of the energy surface because of the presence of enthalpic barriers that originate from out-of-register interactions. The parallel beta-sheet arrangement is favored over the antiparallel because of side-chain contacts; in particular, stacking interactions of the tyrosine rings and hydrogen bonds between amide groups. No ordered aggregation was found in control simulations with the mutant sequence SQNGNQQRG in accord with experimental data and the strong sequence dependence of aggregation.
MH Alanine/chemistry; Amino Acid Sequence; Amino Acid Substitution; Amyloid/*biosynthesis; Fungal Proteins/*chemistry; Prions/*chemistry; Protein Conformation; Support, Non-U.S. Gov't; Tyrosine/chemistry
AD Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
SP englisch
PO USA