Effect of denaturant and protein concentrations upon protein refolding andaggregation: A simple lattice model

We present a study of the competition between protein refolding and aggrega tion for simple lattice model proteins. The effect of solvent conditions (i .e., the denaturant concentration and the protein concentration) on the fol ding and aggregation behavior of a system of simple, two-dimensional lattic e protein molecules has been investigated via dynamic Monte Carlo simulatio ns. The population profiles and aggregation propensities of the nine most p opulated intermediate configurations exhibit a complex dependence on the so lution conditions that can be understood by considering the competition bet ween intra- and interchain interactions. Some of these configurations are n ot even seen in isolated chain simulations; they are observed to be highly aggregation prone and are stabilized primarily by the aggregation reaction in multiple-chain systems. Aggregation arises from the association of parti ally folded intermediates rather than from the association of denatured ran dom-coil states. The aggregation reaction dominates over the folding reacti on at high protein concentration and low denaturant concentration, resultin g in low refolding yields at these conditions. However, optimum folding con ditions exist at which the refolding yield is a maximum, in agreement with some experimental observations.