Aggregated yet Disordered: A Molecular Simulation Study of the Self-Aggregation of Elastin

Abstract

Elastin is the protein responsible for the elastic recoil of skin, arteries, and lungs. Elastin exhibits high resilience and remarkable durability; it also undergoes phase separation and self-organization into a fibrillar structure upon increasing temperature. These properties make elastin ideal for biomaterials applications. In order to investigate the molecular basis for elastin self-aggregation, we performed extensive atomistic molecular dynamics simulations of a monomer and an aggregate of eight elastin-like peptides in explicit water. These simulations required a total time of nearly 0.5 ms, and utilized simulated tempering distributed replica sampling, a method that relies on a random walk in temperature to enhance conformational sampling. We obtain a configurational ensemble of the elastin-like aggregate that resembles a “polymer melt” in which the chains are completely entangled with each other, but retain significant hydration and do not form a water-excluding hydrophobic core. Within the aggregate, the chains act to “solvate” each other: intramolecular interactions present in the monomer in aqueous solution are largely replaced by intermolecular interactions in the aggregate. As a result, the overall chain dimensions are similar to the expected dimensions of chains in an ideal solvent, a state in which chain entropy is maximized. This is the prediction of the Flory theorem for generic polymer chains within a polymer melt, but has never, to our knowledge, been observed before for an aggregate of polypeptide chains in atomistic detail. Finally, we note that our results are not consistent with the current model of elastin self-aggregation, which involves a conformational transition of a monomer towards a more “ordered” aggregation-prone state. Instead, we propose a model in which both the hydrophobic effect and the enhanced chain entropy afforded by the interactions with other peptides within the aggregate favour elastin self-aggregation.