Thermodynamics of Protein-Protein and Peptide Interactions

Summary

Direct measurement of thermodynamic parameters for association/dissociation of proteins and peptides in solution is now routine using isothermal microcalorimetry (ITC) titration and dilution techniques. Examples are given of measurements involving membrane receptors (colicin/porin), protein subunit assemblies insulin, pyruvate dehydrogenase), vancomycin- peptide and synthetic receptors, and peptide “tapes”. Limited kinetic information may also be obtained from calorimetric experiments. Although measurement of thermal data is relatively straightforward, interpretation and rationalisation of the parameters is frustrated by entropy-enthalpy compensation effects. Large variations in enthalpy (ΔH) and entropy (ΔS) of association frequently compensate to give significantly smaller changes in free energy (ΔG), indeed this familiar and ubiquitous homeostatic effect may be of considerable biological advantage in stabilising self-assembling systems against mutation or environmental changes. Nevertheless, the molecular basis for the phenomenon remains something of a mystery. Partly it arises because of the limited ΔG “window” available experimentally, which implies some large-scale apparent so much in the first place. Temperature dependencies may be rationalised in terms of large heat capacity (ΔC_p) effects, which themselves are a manifestation of the thermodynamics of systems comprising multiple, weak (< kT) interactions. Macromolecular conformational dynamics and “quantum confinement” effects can also contribute.