An Artificial Chaperone Serves a Dual Role in Regulating the Assembly of
Peptides through Phase Separation
Abstract
In biological systems, molecular assembly primarily relies on the
assistance of molecular chaperones. Inspired by nature, strategies like
‘chaperone-assisted assembly’ and ‘catalyzed assembly’ have been
proposed towards the sophisticated control of molecular assembly.
Nonetheless, significant challenges remain in the rational design of
such systems, calling for a deep understanding of underlying principles.
Herein, we demonstrate an artificial chaperone serves a dual role, i.e.
catalyst in low dosages and inhibitor in high dosages, in regulating the
supramolecular polymerization of peptides. Low dosages of carboxymethyl
cellulose, as the chaperones, catalyse the assembly of Aβ16-22 peptides
into fibrils through multi-step phase separation, while high dosages
trap the peptides into coacervate intermediates and therefore inhibit
the fibrillation. Consequently, the quantity of chaperone does not
follow the intuition that ‘more is better’ for catalyzing assembly, but
instead has an optimal molar ratio. Investigation reveals that the
interplay and evolution of electrostatic and hydrophobic interactions
between chaperones and peptides are the keys to achieving these
processes. This study provides insights into the multifaceted roles
artificial chaperones may play in a dosage-dependent manner, and
enriches the toolkit for efficient and controllable construction of
complex assembly systems.