Kinetic Control of Parallel versus Antiparallel Amyloid Aggregation via Shape of the Growing Aggregate

Ali Asghar Hakami Zanjani,Nicholas P Reynolds,Joshua T Berryman,Afang Zhang,Raffaele Mezzenga,Tanja Schilling

doi:10.1038/s41598-019-52238-x

Abstract

By combining atomistic and higher-level modelling with solution X-ray diffraction we analyse self-assembly pathways for the IFQINS hexapeptide, a bio-relevant amyloid former derived from human lysozyme. We verify that (at least) two metastable polymorphic structures exist for this system which are substantially different at the atomistic scale, and compare the conditions under which they are kinetically accessible. We further examine the higher-level polymorphism for these systems at the nanometre to micrometre scales, which is manifested in kinetic differences and in shape differences between structures instead of or as well as differences in the small-scale contact topology. Any future design of structure based inhibitors of the IFQINS steric zipper, or of close homologues such as TFQINS which are likely to have similar structures, should take account of this polymorphic assembly.

Highlights

The hydrogen-bonding, hydrophobic and electrostatic interactions which stabilise globular proteins can drive the formation of tough multi-chain ‘amyloid’ aggregates which are often associated in biology with disease[1,2]
VQIINK homologue hexapeptides of IFQINS, and effectiveness of inhibitor design was improved by targeting the polymorphic steric zippers for VQIVYK and VQIINK14, including structural information from soluble nanocrystal or fibril structures as well as from microcrysytals amenable to solid-phase crystallography
We examine solution scattering taken during the aggregation process at high peptide concentration in water which shows an aggregated structure for IFQINS that is consistent with a solid-phase crystal structure previously published, but which is different to the solution scattering previously observed

Summary

Introduction

The hydrogen-bonding, hydrophobic and electrostatic interactions which stabilise globular proteins can drive the formation of tough multi-chain ‘amyloid’ aggregates which are often associated in biology with disease[1,2]. Tau includes the VQIVYK and VQIINK homologue hexapeptides of IFQINS, and effectiveness of inhibitor design was improved by targeting the polymorphic steric zippers for VQIVYK and VQIINK14, including structural information from soluble nanocrystal or fibril structures as well as from microcrysytals amenable to solid-phase crystallography. Effective design of inhibitors for human lysozyme aggregation should benefit from understanding of IFQINS polymorphic steric zippers. One of the motivations to consider amyloid as a biomaterial is the potential for versatility in material properties driven by polymorphism at the atomistic or mesoscopic levels: it is common that a given sequence can stably take on a variety of morphologies[19] including filaments[20], nanotubes[21], helical ribbons[9,11,22], twisted ribbons[11,22] and crystals[11,23] depending on the growth conditions. The experimental data contrasting these two polymorphic structures which differ in the symmetry of assembly allows us to extend our modelling of the hexapeptide aggregation process and examine the physics of selection between polymorphs formed from P and AP β sheet

Methods

Results

Conclusion