Assemblies of peptides
and proteins through specific
intermolecular
interactions set the basis for macroscopic materials found in nature.
Peptides provide easily tunable hydrogen-bonding interactions, which
can lead to the formation of ordered structures such as highly stable
β-sheets that can form amyloid-like supramolecular peptide nanofibrils
(PNFs). PNFs are of special interest, as they could be considered
as mimics of various fibrillar structures found in nature. In their
ability to serve as supramolecular scaffolds, they could mimic certain
features of the extracellular matrix to provide stability, interact
with pathogens such as virions, and transduce signals between the
outside and inside of cells. Many PNFs have been reported that reveal
rich bioactivities. PNFs supporting neuronal cell growth or lentiviral
gene transduction have been studied systematically, and their material
properties were correlated to bioactivities. However, the impact of
the structure of PNFs, their dynamics, and stabilities on their unique
functions is still elusive. Herein, we provide a microscopic view
of the self-assembled PNFs to unravel how the amino acid sequence
of self-assembling peptides affects their secondary structure and
dynamic properties of the peptides within supramolecular fibrils.
Based on sequence truncation, amino acid substitution, and sequence
reordering, we demonstrate that peptide–peptide aggregation
propensity is critical to form bioactive β-sheet-rich structures.
In contrast to previous studies, a very high peptide aggregation propensity
reduces bioactivity due to intermolecular misalignment and instabilities
that emerge when fibrils are in close proximity to other fibrils in
solution. Our multiscale simulation approach correlates changes in
biological activity back to single amino acid modifications. Understanding
these relationships could lead to future material discoveries where
the molecular sequence predictably determines the macroscopic properties
and biological activity. In addition, our studies may provide new
insights into naturally occurring amyloid fibrils in neurodegenerative
diseases