Role of water in Protein Aggregation and Amyloid Polymorphism

Details Role of water in Protein Aggregation and Amyloid Polymorphism Role of water in Protein Aggregation and Amyloid Polymorphism

2011-07-25

arxiv.org/abs/1107.4820v1

Physics

Condensed Matter

Soft Condensed Matter

27 pages, 4 figures; Accounts of Chemical Research, 2011

Scientific paper

10.1021/ar2000869

A variety of neurodegenerative diseases are associated with the formation of amyloid plaques. Our incomplete understanding of this process underscores the need to decipher the principles governing protein aggregation. Most experimental and simulation studies have been interpreted largely from the perspective of proteins: the role of solvent has been relatively overlooked. In this Account, we provide a perspective on how interactions with water affect folding landscapes of A$\beta$ monomers, A$\beta_{16-22}$ oligomer formation, and protofilament formation in a Sup35 peptide. Simulations show that the formation of aggregation-prone structures (N$^*$) similar to the structure in the fibril requires overcoming high desolvation barrier. The mechanism of protofilament formation in a polar Sup35 peptide fragment illustrates that water dramatically slows down self-assembly. Release of water trapped in the pores as water wires creates protofilament with a dry interface. Similarly, one of the main driving force for addition of a solvated monomer to a preformed fibril is the entropy gain of released water. We conclude by postulating that two-step model for protein crystallization must also hold for higher order amyloid structure formation starting from N$^*$. Multiple N$^*$ structures with varying water content results in a number of distinct water-laden polymorphic structures. In predominantly hydrophobic sequences, water accelerates fibril formation. In contrast, water-stabilized metastable intermediates dramatically slow down fibril growth rates in hydrophilic sequences.

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