Prion-like Aggregation of the Heptapeptide GNNQQNY into Amyloid Nanofiber Is Governed by Configuration Entropy

A major cause of prion infectivity is the early formation
of small,
fibril-like aggregates consisting of the heptapeptide GNNQQNY. The
prion aggregates exhibit a unique stacking mode in which the hydrophobic
tyrosine (Y) is exposed outward, forming a bilayer β-sheet-stacking
zipper structure. This stacking mode of the prion peptides, termed
“Y-outward” structure for convenience, goes against
the common understanding that, for other amyloid-forming peptides,
the hydrophobic residues should be hidden within the peptide fibril,
referred to as “Y-inward” structure. To explore the
extraordinary stacking behaviors of the prion GNNQQNY peptides, two
fibril models are constructed in a fashion of “Y-outward”
and “Y-inward” stackings and then studied in
silico to examine their thermodynamic stabilities and disaggregation
pathways. The “Y-inward” structure indeed exhibits stronger
thermodynamic stability than the “Y-outward” structure,
according to potential energy and stacking energy calculations. To
show how the peptide fibrils dissociate, we illustrated two disaggregation
pathways. A dihedral-based free energy landscape was then calculated
to examine the conformational degrees of freedom of the GNNQQNY chains
in the “Y-outward” and “Y-inward” structures.
Peptide chains lose more configurational entropy in the “Y-inward”
structure than in the “Y-outward” structure, indicating
that the prion peptides are prone to aggregate in a fashion of “Y-outward”
stacking pattern due to its low conformational constraints. The prion-like
aggregation of the GNNQQNY peptides into amyloid fibrils is primarily
governed by the configuration entropy.