An analysis of the thermodynamics of protein stability reveals a general te
ndency for proteins that denature at higher temperatures to have greater fr
ee energies of maximal stability. To a reasonable approximation, the temper
ature of maximal stability for the set of globular, water-soluble proteins
surveyed by Robertson and Murphy occurs at T* similar to 283K, independent
of the heat denaturation temperature, T-m. This observation indicates, at l
east for these proteins, that thermostability tends to be achieved through
elevation of the stability curve rather than by broadening or through a hor
izontal shift to higher temperatures. The relationship between the free ene
rgy of maximal stability and the temperature of heat denaturation is such t
hat an increase in maximal stability of similar to0.008 kJ/mole/residue is,
on average, associated with a 1 degreesC increase in T-m. An estimate of t
he energetic consequences of thermal expansion suggests that these effects
may contribute significantly to the destabilization of the native state of
proteins with increasing temperature.