Portal de Periódicos da CAPES

Extent of enthalpy–entropy compensation in protein–ligand interactions

2011; Wiley; Volume: 20; Issue: 9 Linguagem: Inglês

10.1002/pro.692

1469-896X

Tjelvar S. G. Olsson, John E. Ladbury, William R. Pitt, Mark A. Williams,

Chemical Thermodynamics and Molecular Structure

Abstract The extent of enthalpy–entropy compensation in protein–ligand interactions has long been disputed because negatively correlated enthalpy (Δ H ) and entropy ( T Δ S ) changes can arise from constraints imposed by experimental and analytical procedures as well as through a physical compensation mechanism. To distinguish these possibilities, we have created quantitative models of the effects of experimental constraints on isothermal titration calorimetry (ITC) measurements. These constraints are found to obscure any compensation that may be present in common data representations and regression analyses (e.g., in Δ H vs. – T Δ S plots). However, transforming the thermodynamic data into ΔΔ‐plots of the differences between all pairs of ligands that bind each protein diminishes the influence of experimental constraints and representational bias. Statistical analysis of data from 32 diverse proteins shows a significant and widespread tendency to compensation. ΔΔ H versus ΔΔG plots reveal a wide variation in the extent of compensation for different ligand modifications. While strong compensation (ΔΔ H and − T ΔΔ S opposed and differing by < 20% in magnitude) is observed for 22% of modifications (twice that expected without compensation), 15% of modifications result in reinforcement (ΔΔ H and − T ΔΔ S of the same sign). Because both enthalpy and entropy changes arise from changes to the distribution of energy states on binding, there is a general theoretical expectation of compensated behavior. However, prior theoretical studies have focussed on explaining a stronger tendency to compensation than actually found here. These results, showing strong but imperfect compensation, will act as a benchmark for future theoretical models of the thermodynamic consequences of ligand modification.