Structure and dynamics of confined water in amyloid protein fibril nanochannels

Many fibrils of amyloid proteins are characterized by a dense core structure that largely excludes water. However, an increasing number of amyloid fibril structures are observed to contain water channels. Although water in membrane protein channels and pores has been studied, the structure and dynamics of water in amyloid protein fibril nanochannels is largely unexplored. In this computational study, we used molecular dynamics simulations to characterize the structure and dynamics of water inside the water channels of ex vivo human Serum Amyloid A (hSAA), ex vivo murine SAA (mSAA), and ex vivo feline SAA (fSAA) fibrils. Although these proteins are highly homologous, their fibril architectures differ substantially, providing an opportunity to understand how sequence-level variation influences interior water behavior. We find that water within the channels of all three fibrils exhibits damped translational and rotational diffusion relative to bulk water and adopts distinct ordered hydrogen-bonding networks. The water in fSAA and hSAA channels hydrates interior salt-bridges and hydrogen bonds with hydrophilic side chains, suggesting a stabilizing role. Confined water in mSAA channels engages in interactions with both the side chains and backbone of the residues, showing a unique trigonal arrangement and ice-like dynamics that has not been previously reported for confined water. Our results serve to elucidate the structural and dynamical role of water in the interior of amyloid protein fibrils.