Role of Water in Protein Aggregation and Amyloid Polymorphism

Abstract

Conspectus The link between oligomers and amyloid fibrils and a variety of neurodegenerative diseases raises the need to decipher the principles governing protein aggregation. Mechanisms of in vivo amyloid formation involve a number of coconspirators and complex interactions with membranes. Nevertheless, it is believed that understanding the biophysical basis of in vitro amyloid formation in well-defined systems is important in discovering ligands that preferentially bind to regions that harbor amyloidogenic tendencies. Determination of structures of fibrils of a variety of peptides has set the stage for probing the dynamics of oligomer formation and amyloid growth using computer simulations. Most experimental and simulation studies have been interpreted largely from the perspective of proteins without much consideration of the role of solvent in enabling or inhibiting oligomer formation and assembly to protofilaments and amyloid fibrils. Here, we provide a perspective on how interactions with water affect folding landscapes of Aβ monomers, oligomer formation in Aβ16–22 fragment, protofilament formation in a peptide from yeast prion Sup35. Explicit molecular dynamics simulations of these systems illustrate how water controls the self-assembly of higher order structures and provide a structural basis for understanding the kinetics of oligomer and fibril growth. Simulations show that monomers of Aβ-peptides sample a number of compact conformations. Population of aggregation-prone structures (N*) with salt-bridge, which bear a striking similarity to the peptide structure in the fibril, requires overcoming a high desolvation barrier. In general, sequences for which N* structures are not significantly populated are unlikely to aggregate. Generically oligomers and fibrils form in two steps. In the first stage water is expelled from the region between peptides rich in hydrophobic residues (for example Aβ16–22) resulting in the disordered oligomers. In the second stage, the peptides align along a preferred axis to form ordered structures with anti-parallel β-strand arrangement. The rate limiting step in the ordered assembly is the rearrangement of the peptides within a confining volume. The mechanism of protofilament formation in a polar peptide fragment from the yeast prion in which the two sheets are packed against each other creating a dry interface illustrates that water dramatically slows down self-assembly. As the sheets approach each other two perfectly ordered one-dimensional water wires, which are stabilized by hydrogen bonds to the amide groups of the polar side chains, results in the formation of long-lived metastable structures. Release of the trapped water from the pore creates a helically-twisted protofilament with a dry interface. Similarly, the driving force for addition of a solvated monomer to a preformed fibril is the release of water whose entropy gain and favorable inter peptide hydrogen bond formation compensates for loss in entropy of the peptides. We suggest that the two-step mechanism, a model a...

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