Unravelling the Complexity of Amyloid Peptide Core Interfaces

Amyloids, large intermolecular sandwiched β-sheet
structures,
underlie several protein misfolding diseases but have also been shown
to have functional roles and can be a basis for designing smart and
responsive nanomaterials. Short segments of proteins, called aggregation-prone
regions (APRs), have been identified that nucleate amyloid formation.
Here we present the database of 173 APR crystal structures currently
available in the PDB, and a tool, ACW, for analyzing their topologies
and the 267 inter-β-sheet interfaces of zipper regions assigned
in these structures. We defined a new descriptor of zipper interfaces,
the surface detail index (SDi), which quantifies the intertwining
between the side chains of both β-sheets of the zipper, an important
factor for the molecular recognition and self-assembly of these mesostructures.
This allowed a comparative analysis of the zipper interfaces and identification
of 6 clusters with different intertwining, steric fit, and size characteristics
using three complementary descriptors, SDi, shape complementarity,
and buried surface area. 60% of the APR structures are formed by parallel
β-sheets, of which 52% belong to the topological class 1. This
could be explained by the better fit and a deeper entanglement of
the zipper regions of the parallel structures than of the antiparallel
structures, as the analysis showed that both their shape complementarity
(0.79 vs 0.70) and SDi (1.53 vs 1.32) were higher. The higher abundance
of certain residues (Asn and Gln in parallel and Leu and Ala in antiparallel
β-sheets) can be explained by their ability to form different
ladder-like secondary interaction patterns within β-sheets.
Analogous to the hierarchy of protein structure, we interpreted the
primary, secondary, tertiary, and quaternary structure levels of APRs
revealing different characteristics of the zipper regions for both
parallel and antiparallel β-sheet structures, which may provide
clues to the structural conditions of amyloid core formation and the
rational design of amyloid polymorphs.