Krausser, J. | Search bioRxiv

bioRxiv2020

Designing membrane-reshaping nanostructures through artificial evolution

In this paper we combine the rules of natural evolution with molecular dynamics simulations to design a nanostructure with a desired function. We apply this scheme to the case of a ligand-covered nanoparticle and evolve ligand patterns that promote efficient cell uptake. Surprisingly, we find that in the regime of low ligand number the fittest structures are characterised by ligands arranged into long one-dimensional chains that pattern the surface of the particle. We show that these chains of ligands provide particles with high rotational freedom and they lower the free energy barrier for membrane crossing. This demonstrates the efficacy of artificial evolution to identify non-intuitive design rules and reveals a new principle of design that can be used to inform artificial nanoparticle construction and the search for inhibitors of viral entry.

biophysics↗

bioRxiv2019

Physical mechanisms of amyloid nucleation on fluid membranes

Biological membranes can dramatically accelerate the aggregation of normally soluble protein molecules into amyloid fibrils and alter the fibril morphologies, yet the molecular mechanisms through which this accelerated nucleation takes place are not yet understood. Here, we develop a coarse-grained model to systematically explore the effect that the structural properties of the lipid membrane and the nature of protein-membrane interactions have on the nucleation rates of amyloid fibrils. We identify two physically distinct nucleation pathways and quantify how the membrane fluidity and protein-membrane affinity control the relative importance of those molecular pathways. We find that the membranes susceptibility to reshaping and being incorporated into the fibrillar aggregates is a key determinant of its ability to promote protein aggregation. We then characterise the rates and the free energy profile associated to this heterogeneous nucleation process in which the surface itself participates in the aggregate structure. Finally, we compare quantitatively our data to experiments on membrane-catalysed amyloid aggregation of -synuclein, a protein implicated in Parkinsons disease that predominately nucleates on membranes. More generally, our results provide a framework for understanding macromolecular aggregation on lipid membranes in a broad biological and biotechnological context.

biophysics↗