Assembly and kinetic folding pathways of a tetrameric beta-sheet complex: molecular dynamics simulations on simplified off-lattice protein models.

We have performed discontinuous molecular dynamic simulations of the assembly and folding kinetics of a tetrameric beta-sheet complex that contains four identical four-stranded antiparallel beta-sheet peptides. The potential used in the simulation is a hybrid Go-type potential characterized by the bias gap parameter g, an artificial measure of a model protein's preference for its native state, and the intermolecular contact parameter eta, which measures the ratio of intermolecular to intramolecular native attractions. The formation of the beta-sheet complex and its equilibrium properties strongly depend on the size of the intermolecular contact parameter eta. The ordered beta-sheet complex in the folded state and nonaligned beta-sheets or tangled chains in the misfolded state are distinguished by measuring the squared radius of gyration Rg2 and the fraction of native contacts Q. The folding yield for the folded state is high at intermediate values of eta, but is low at both small and large values of eta. The folded state at small eta is liquid-like, but is solid-like at both intermediate and large eta. The misfolded state at small eta contains nonaligned beta-sheets and tangled chains with poor secondary structure at large eta. Various folding pathways via dimeric and trimeric intermediates are observed, depending on eta. Comparison with experimental results on protein aggregation indicates that intermediate eta values are most appropriate for modeling fibril formation and small eta values are most appropriate for modeling the formation of amorphous aggregates.