Stability Threshold as a Selection Principle for Protein Design

The sensitivity of the native states of proteinlike heteropolymers to mutations modeled as perturbations in the interaction potential between amino acids is studied. The stability threshold against mutations is shown to be zero for random heteropolymers on a lattice in two dimensions, whereas a design procedure modeling evolution produces a nonzero threshold. We introduce an evolutionlike protein design procedure based on an optimization of the stability threshold that is shown to naturally ensure thermodynamic stability as well.