Issue 44, 2020

Aggregation propensity of therapeutic fibrin-homing pentapeptides: insights from experiments and molecular dynamics simulations

Abstract

CREKA (Cys–Arg–Glu–Lys–Ala) and its engineered analogue CRMeEKA, in which Glu has been replaced by N-methyl-Glu to provide resistance against proteolysis, are emerging pentapeptides that were specifically designed to bind fibrin–fibronectin complexes accumulated in the walls of tumour vessels. However, many of the intrinsic properties of CREKA and CRMeEKA, which are probably responsible for their different behaviour when combined with other materials (such as polymers) for diagnosis and therapeutics, remain unknown yet. The intrinsic tendency of these pentapeptides to form aggregates has been analysed by combining experimental techniques and atomistic Molecular Dynamics (MD) simulations. Dynamic light scattering assays show the formation of nanoaggregates that increase in size with the peptide concentration, even though aggregation occurs sooner for CRMeEKA, independently of the peptide concentration. FTIR and circular dichroism spectroscopy studies suggest that aggregated pentapeptides do not adopt any secondary structure. Atomistic MD trajectories show that CREKA aggregates faster and forms bigger molecular clusters than CRMeEKA. This behaviour has been explained by stability of the conformations adopted by un-associated peptide strands. While CREKA molecules organize by forming intramolecular backbone – side chain hydrogen bonds, CRMeEKA peptides display main chain – main chain hydrogen bonds closing very stable γ- or β-turns. Besides, energetic analyses reveal that CRMeEKA strands are better solvated in water than CREKA ones, independent of whether they are assembled or un-associated.

Graphical abstract: Aggregation propensity of therapeutic fibrin-homing pentapeptides: insights from experiments and molecular dynamics simulations

Supplementary files

Article information

Article type
Paper
Submitted
20 Maijs 2020
Accepted
21 Okt. 2020
First published
22 Okt. 2020

Soft Matter, 2020,16, 10169-10179

Aggregation propensity of therapeutic fibrin-homing pentapeptides: insights from experiments and molecular dynamics simulations

D. Zanuy, A. Puiggalí-Jou, P. Conflitti, G. Bocchinfuso, A. Palleschi and C. Alemán, Soft Matter, 2020, 16, 10169 DOI: 10.1039/D0SM00930J

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