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

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.

Novel self-assembling cyclic peptides with reversible supramolecular nanostructures

“…Molecular dynamics simulations, both atomistic and coarse-grained (CG), have been used in combination with Morphoscanner 52 for studying the self-assembling process of cyclic peptides, adopting a similar protocol to that adopted for other classes of peptides. 53,54 The atomistic molecular dynamics simulations of the cycle peptides unveiled conformational heterogeneity (Fig. 4a).…”

Efficient analysis of pharmaceutical drug substances and products using a solid-state NMR CryoProbe

“…The CPMAS CryoProbe has been recently applied to characterize biological materials. [41][42][43] In the present study, we carefully examined the sensitivity enhancement of the CryoProbe. Fig.…”

“…Most recently, the cryogenically cooled MAS probe (CPMAS CryoProbe™, Bruker Biospin) has been reported for the structural studies of proteins with improved sensitivity. [41][42][43] Hassan et al demonstrated 3-4 fold sensitivity enhancement on heteronuclear-detected ssNMR experiments for the investigations of a wide variety of large and complex biological systems using the CPMAS CryoProbe. 42 Moreover, Lau et al integrated the CPMAS CryoProbe and X-ray diffraction (XRD) to study the structure of surfactant-like peptide fibrils, and more than 50 intermolecular peptide-peptide contacts were observed by 2D 13 C- 13 C ssNMR owing to the sensitivity boost.…”

“…42 Moreover, Lau et al integrated the CPMAS CryoProbe and X-ray diffraction (XRD) to study the structure of surfactant-like peptide fibrils, and more than 50 intermolecular peptide-peptide contacts were observed by 2D 13 C- 13 C ssNMR owing to the sensitivity boost. 41 CryoProbe offers an opportunity for a more efficient analysis of pharmaceutical solids by enhanced 13 C and 15 N sensitivity. Here, we applied the CPMAS CryoProbe for the structural investigation of a naturally abundant pharmaceutical compound, POSA, in its crystalline and amorphous forms as well as a 30 wt% drugloaded ASD.…”

The Martini Model in Materials Science

“…[ 229 ] Many groups have explored their self‐assembly process by leveraging the Martini model. [ 230–252 ] Besides allowing simulation of the self‐assembly and growth, Martini is also particularly suited for high‐throughput applications. An example of such a high‐throughput application in the area of peptide‐based supramolecular materials is the work of Frederix et al.…”