Using lattice models we explore the factors that determine the tendencies of polypeptide chains to aggregate by exhaustively sampling the sequence and conformational space. The morphologies of the fibril-like structures and the time scales (${\tau }_{\mathrm{fib}}$) for their formation depend on a balance between hydrophobic and Coulomb interactions. The extent of population of an ensemble of ${\mathbf{N}}^{*}$ structures, which are fibril-prone structures in the spectrum of conformations of an isolated protein, is the major determinant of ${\tau }_{\mathrm{fib}}$. This observation is used to determine the aggregating sequences by exhaustively exploring the sequence space, thus providing a basis for genome wide search of fragments that are aggregation prone.

• Received 17 October 2009

DOI:https://doi.org/10.1103/PhysRevLett.105.218101