Unravelling the\nComplexity of Amyloid Peptide Core\nInterfaces

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