Protein Heat Capacity: An Anomaly that Maybe Never Was

Protein unfolding in aqueous solution is usually accompanied by an increase in heat capacity (Δ C p ), and this has long been regarded as somewhat anomalous. However, neither the absolute heat capacities ( C p ) of folded globular proteins nor the heat capacity increments upon unfolding (Δ C p ) are unusual in comparison to values observed for order−disorder (melting) transitions in other organic substances. The consequences for protein stability, including cold denaturation, enthalpy−entropy compensation, and the temperature of maximum stability, may seem counterintuitive but should not be unexpected. Nevertheless, while perhaps not so anomalous as once thought, quantitative interpretation of protein heat capacity and related effects remains a theoretical challenge.