jp503742p_si_001.pdf (1.28 MB)
Combining Classical MD and QM Calculations to Elucidate Complex System Nucleation: A Twisted, Three-Stranded, Parallel β‑Sheet Seeds Amyloid Fibril Conception
journal contribution
posted on 2014-07-03, 00:00 authored by Miguel Mompeán, Carlos González, Enrique Lomba, Douglas V. LaurentsThe crystal structure of the Sup35
prion segment, GNNQQNY, revealed
precise side chain packing and an extensive H-bond network. However,
the conformers and stabilizing interactions involved at nascent amyloid
formation are still unclear. Here, long molecular dynamics simulations
and quantum mechanical calculations have been utilized to study the
conformation and energetics of the initial structure that acts to
nucleate further growth. Considering all the plausible intermediates
that may act as stepping stones, we find that the initial nucleus
is a twisted single-layer, three-stranded parallel β-sheet.
H-bonds between β-strands in this twisted sheet, some of which
differ from those of the crystal structure’s nontwisted β-strands,
are key for the nucleus’ formation and stability. High level
theoretical calculations of these H-bonds’ energetics can account
for this amyloid-like trimer’s remarkable stability. The intermeshing
of facing sheets to form the dry interface provides less stability
and would occur between two three-stranded β-sheets without
metastable water nanowires.