Effect of secondary structure on protein aggregation: A replica exchange simulation study

The ability to control or reverse protein aggregation is vital to the production and formulation of therapeutic proteins and may be the key to the prevention of a number of neurodegenerative diseases. In recent years, laboratory studies of the phenomenon have been accompanied by a growing number of computational treatments aimed at elucidating the molecular mechanisms of aggregation. The present article is a continuation of our simulation studies of coarse-grained model oligopeptides that mimic aggregating proteins. The potential function of a multichain system is expressed in terms of a generalized Go model for a set of sequences with varying contents of secondary-structural motifs akin to alpha-helices and beta-sheets. Conformational evolution is considered by conventional Monte Carlo simulation, and by a variation of the Replica Monte Carlo technique that facilitates barrier-crossing in glasslike aggregated systems. The foldability and aggregation propensity are monitored as functions of the extent of different secondary structures and the length of the chains. Our results indicate that an increased proportion of sheetlike structures facilitates folding of isolated chains, but strongly favors the formation of misfolded aggregates in multichain systems, in agreement with experimental observations. This behavior is interpreted in terms of cooperativity effects associated with the formation of multiple residue-residue bonds involving adjacent monomers in interacting segments, which enhance both intramolecular binding and interprotein association. (C) 2003 American Institute of Physics.