Control over the fibrillization yield by varying the oligomeric nucleation propensities of self-assembling peptides

Katrien Remaut,Wim E Hennink,Enrico Mastrobattista,Heyang Zhang,Laurens D B Mandemaker,Alia Hassan,João Medeiros-Silva,Barbara Perrone,Rainer Kuemmerle,Chun Yin Jerry Lau,Joep Van Den Dikkenberg,Alexandre M J J Bonvin,Federico Fontana,Benjamin Vermeer,Renko De Vries,Dennie Wezendonk,Markus Weingarth,Fabrizio Gelain

doi:10.1038/s42004-020-00417-7

Abstract

Self-assembling peptides are an exemplary class of supramolecular biomaterials of broad biomedical utility. Mechanistic studies on the peptide self-assembly demonstrated the importance of the oligomeric intermediates towards the properties of the supramolecular biomaterials being formed. In this study, we demonstrate how the overall yield of the supramolecular assemblies are moderated through subtle molecular changes in the peptide monomers. This strategy is exemplified with a set of surfactant-like peptides (SLPs) with different β-sheet propensities and charged residues flanking the aggregation domains. By integrating different techniques, we show that these molecular changes can alter both the nucleation propensity of the oligomeric intermediates and the thermodynamic stability of the fibril structures. We demonstrate that the amount of assembled nanofibers are critically defined by the oligomeric nucleation propensities. Our findings offer guidance on designing self-assembling peptides for different biomedical applications, as well as insights into the role of protein gatekeeper sequences in preventing amyloidosis.

Highlights

Self-assembling peptides are an exemplary class of supramolecular biomaterials of broad biomedical utility
Using combined experimental techniques and molecular dynamics (MD) simulations, we demonstrate that these two molecular parameters (i.e., β-sheet propensities and charged residues flanking the aggregation domains) can modulate both the nucleation propensity of the oligomeric intermediates and the thermodynamic stability of the fibril structures
We evaluated the thermodynamic stability of the fibril models using steered MD (SMD) simulations

Summary

Introduction

Self-assembling peptides are an exemplary class of supramolecular biomaterials of broad biomedical utility. Increasing evidence shows that, to overcome the huge desolvation barrier, rather than a spontaneous thermodynamic process, supramolecular assembly of amphiphilic peptides proceed via a multistep[11] pathway, along which metastable oligomeric states are first formed before conversion to supramolecular nanofibers (Fig. 1a)[12,13,14,15,16,17,18]. This implies that the state of the intermediates in the assembly pathway exert critical influence over the outcome of the peptide self-assembly[19,20]. Despite progress in the mechanistic understanding, the interrelationship between the molecular properties of the peptide monomers, the oligomeric intermediates and the overall yield of the supramolecular assembly process remains largely elusive[22]

Methods

Results

Conclusion