The rugged folding landscapes of functional proteins puts them at risk of misfolding and aggregation.
Serine protease inhibitors, or serpins, are paradigms for this delicate balance between function and
misfolding. Serpins exist in a metastable state that undergoes a major conformational change in
order to inhibit proteases. However, conformational labiality of the native serpin fold renders them
susceptible to misfolding, which underlies misfolding diseases such as α1-antitrypsin deficiency. To
investigate how serpins balance function and folding, we used consensus design to create conserpin,
a synthetic serpin that folds reversibly, is functional, thermostable, and polymerization resistant.
Characterization of its structure, folding and dynamics suggest that consensus design has remodeled
the folding landscape to reconcile competing requirements for stability and function. This approach
may offer general benefits for engineering functional proteins that have risky folding landscapes,
including the removal of aggregation-prone intermediates, and modifying scaffolds for use as protein
therapeutics