Probing the structural and functional link between mutation- and pH-dependent hydration dynamics and amyloidosis of transthyretin

Abstract

Protein surface hydration, providing a flexible matrix enabling the protein to respond efficiently to environmental changes, is central to its folding, structure and stability. The aberrant folding of proteins links with a huge variety of diseases, such as prion diseases, diabetes and cancer. Considering the correlation between the mechanism by which a polypeptide chain folds to a specific three-dimensional protein structure, and the role of hydration in the aggregation of misfolded proteins, we use 23 large-scale molecular dynamics simulations to study the local hydration dynamics at the surface of transthyretin (TTR), a thyroid hormone-binding protein that transports thyroxine from the bloodstream to the brain. Monitoring the effects of solvent dynamical behavior around specific mutations by density and spatial distribution entropy maps of the solvent identifies two kinds of water: (1) the hydration water surrounding the stability-bearing mutations characterized by long residential time and slow diffusion; and (2) the water adjacent to the amyloidogenic mutations in fast exchange with the bulk water. Alternative conformations of the protein induced by mutations govern the solvent dynamical behaviors, further evidenced by a map of the spatial distribution entropy of the solvent around the protein. The special behavior of the solvent around these regions is probably crucial in the folding stability and in terms of aggregation loci. These results are also proven by the global perturbations of the protein hydration shell by acidic pH that exhibits dramatic suppression of the aqueous protein motion, and meanwhile, inactivates the stability-bearing waters. This indicates that the acidic medium destroys the cluster structure of water molecules, inducing water diffusion and protein conformational transformation. The present work opens up a possibility of using the mutation and the pH value as probes for protein folding kinetics and functional dynamics measurements, and provides a clue for the treatment of amyloid diseases associated with TTR misfolding.