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 ($tau_{fib
}$) for their formation depend on a subtle balance between hydrophobic and coulomb interactions. The extent of population of a fibril-prone structure in the spectrum of monomer conformations is the major determinant of $tau_{fib}$. This observation is used to determine the aggregation-prone consensus sequences by exhaustively exploring the sequence space. Our results provide a basis for genome wide search of fragments that are aggregation prone.
Using exhaustive Monte Carlo simulations we study the kinetics and mechanism of fibril formation using lattice models as a function of temperature and the number of chains. While these models are, at best, caricatures of peptides, we show that a numb
er of generic features thought to govern fibril assembly are present in the toy model. The monomer, which contains eight beads made from three letters (hydrophobic, polar, and charged), adopts a compact conformation in the native state. The kinetics of fibril assembly occurs in three distinct stages. In each stage there is a cascade of events that transforms the monomers and oligomers to ordered structures. In the first burst stage highly mobile oligomers of varying sizes form. The conversion to the aggregation-prone conformation occurs within the oligomers during the second stage. As time progresses, a dominant cluster emerges that contains a majority of the chains. In the final stage, the aggregation-prone conformation particles serve as a template onto which smaller oligomers or monomers can dock and undergo conversion to fibril structures. The overall time for growth in the latter stages is well described by the Lifshitz-Slyazov growth kinetics for crystallization from super-saturated solutions.
