Thermodynamic molecular switch in biological systems

It is, of course, known that most living systems can live and operate optimally only at a sharply defined temperature, or over a limited temperature range at best. This implies that many basic biochemical interactions exhibit a well‐defined Gibbs free energy minimum as a function of temperature. Most typical processes of biological molecules or biopolymers show Δ H °( T ) positive (unfavorable) and also a positive Δ S °( T ) (favorable) at low temperature, due to a positive (Δ C p °/ T ). For biological systems Δ G °( T ) shows a complicated behavior, wherein Δ G °( T ) changes from positive to negative, then reaches a negative value of maximum magnitude, and finally becomes positive as temperature increases. This communication demonstrates that the critical factor is a temperature‐dependent Δ C p °( T ) (specific heat capacity change) of reaction that is positive at low temperature but switches to a negative value at a temperature well below the ambient range. This thermodynamic molecular switch determines the behavior patterns of the Gibbs free energy change, and hence a change in the equilibrium constant, K eq , and/or spontaneity. The subsequent, mathematically predictable changes in Δ H °( T ), Δ S °( T ), Δ W °( T ) and Δ G °( T ) give rise to the classically observed behavior patterns in biological reactivity as demonstrated in three interacting protein systems—human DNA ligase I–DNA polymerase β, the fragment complementation reaction of S‐protein‐phe 13‐S‐peptide (M13F‐RNase S′), and glucagon trimerization. In cases of protein unfolding such as the phage T4 phage lysozyme temperature‐sensitive mutants, no thermodynamic molecular switch is observed. © 2000 John Wiley & Sons, Inc. Int J Quant Chem 80: 1181–1198, 2000