Competitive inhibition reaction mechanisms for the two-step model of protein aggregation

•Three mechanisms for competitive inhibition of protein aggregation are introduced.•Rate equations are derived to estimate aggregation inhibition constants.•Rate equations are used to distinguish inhibition mechanisms of insulin aggregation.•Longer insulin peptide inhibitors delay insulin aggregation onset.•Shorter insulin peptide inhibitors reduce total concentration of aggregated insulin.

We propose three new reaction mechanisms for competitive inhibition of protein aggregation for the two-step model of protein aggregation. The first mechanism is characterized by the inhibition of native protein, the second is characterized by the inhibition of aggregation-prone protein and the third mechanism is characterized by the mixed inhibition of native and aggregation-prone proteins. Rate equations are derived for these mechanisms, and a method is described for plotting kinetic results to distinguish these three types of inhibitors. The derived rate equations provide a simple way of estimating the inhibition constant of native or aggregation-prone protein inhibitors in protein aggregation. The new approach is used to estimate the inhibition constants of different peptide inhibitors of insulin aggregation.

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