Microscopic origins of entropy, heat capacity and the glass transition in proteins.

Internal motion is central to protein folding, to protein stability through the resulting residual entropy, and to protein function. Despite its importance, the precise nature of the internal motions of protein macromolecules remains a mystery. Here we report a survey of the temperature dependence of the fast dynamics of methyl-bearing side chains in a calmodulin-peptide complex using site-specific deuterium NMR relaxation methods. The amplitudes of motion had a markedly heterogeneous spectrum and segregated into three largely distinct classes. Other proteins studied at single temperatures tend to segregate similarly. Furthermore, a large variability in the degree of thermal activation of the dynamics in the calmodulin complex indicates a heterogeneous distribution of residual entropy and hence reveals the microscopic origins of heat capacity in proteins. These observations also point to an unexpected explanation for the low-temperature 'glass transition' of proteins. It is this transition that has been ascribed to the creation of protein motional modes that are responsible for biological activity.