One stumbling block in trying to apply thermodynamics rationally is enthalpy-entropy compensation, a perverse trick of the universe in which, when you improve the enthalpy of an interaction, you may worsen entropy, and vice versa. For example, if you introduce a hydrogen bond into a protein-ligand interaction, the precise positioning required may cause increased rigidity, at an entropic cost.
Now a new paper in Proc. Nat. Acad. Sci. USA from Michael Gilson and colleagues at UCSD suggests that things may be even more complicated. They analyze a previously published 1 millisecond molecular dynamics simulation of the small (58 residue) protein BPTI. There are three main conformational states (or clusters), each with similar overall energies. However, the researchers find that the different conformational states have very different global enthalpies and entropies. Worse, very tiny perturbations, such as the distance between two side chain atoms, can cause one state to shift to another, in turn dramatically changing the overall thermodynamic signature.
In practice, this means that when you measure the thermodynamics of a ligand binding to a protein, the enthalpic and entropic changes observed could have more to do with subtle changes in the global conformation of the protein, or even changes in solvent binding, than to the ligand-protein interaction itself.
The researchers call this phenomenon entropy-enthalpy transduction (EET):
The thermodynamic character of a local perturbation, such as enthalpic binding of a small molecule, is camouflaged by the thermodynamics of a global conformational change induced by the perturbation, such as a switch into a high-entropy conformational state.
The researchers argue that EET could occur in many protein systems, so experimentally determined values of entropy and enthalpy for ligand binding are actually unreliable indicators of the local thermodynamic driving forces we normally try to influence.
Although the researchers develop a sophisticated mathematical framework to describe EET, at the end of the article I’m left wondering, is there any hope of using thermodynamics for practical drug discovery?