Ensemble-based signatures of energy propagation in proteins: a new view of an old phenomenon.

The ability of a protein to transmit the energetic effects of binding from one site to another constitutes the underlying basis for allosterism and signal transduction. Despite clear experimental evidence indicating the ability of proteins to transmit the effects of binding, the means by which this propagation is facilitated is not well understood. Using our previously developed ensemble-based description of the equilibrium, we investigated the physical basis of energy propagation and identified several fundamental and general aspects of energetic coupling between residues in a protein. First, partitioning of a conformational ensemble into four distinct sub-ensembles allows for explanation of the range of experimentally observed coupling behaviors (i.e., positive, neutral, and negative coupling between various regions of the protein structure). Second, the relative thermodynamic properties of these four sub-ensembles define the energetic coupling between residues as either positive, neutral, or negative. Third, analysis of the structural and thermodynamic features of the states within each sub-ensemble reveals significant variability. This third result suggests that a quantitative description of energy propagation in proteins requires an understanding of the structural and energetic features of more than just one or a few low-energy states, but also of many high-energy states. Such findings illuminate the difficulty in interpreting energy propagation in proteins in terms of a structural pathway that physically links coupled sites.