  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.
