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Review
.2013:42:121-42.
doi: 10.1146/annurev-biophys-083012-130318.

Entropy-enthalpy compensation: role and ramifications in biomolecular ligand recognition and design

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Review

Entropy-enthalpy compensation: role and ramifications in biomolecular ligand recognition and design

John D Chodera et al. Annu Rev Biophys.2013.

Abstract

Recent calorimetric studies of interactions between small molecules and biomolecular targets have generated renewed interest in the phenomenon of entropy-enthalpy compensation. In these studies, entropic and enthalpic contributions to binding are observed to vary substantially and in an opposing manner as the ligand or protein is modified, whereas the binding free energy varies little. In severe examples, engineered enthalpic gains can lead to completely compensating entropic penalties, frustrating ligand design. Here, we examine the evidence for compensation, as well as its potential origins, prevalence, severity, and ramifications for ligand engineering. We find the evidence for severe compensation to be weak in light of the large magnitude of and correlation between errors in experimental measurements of entropic and enthalpic contributions to binding, though a limited form of compensation may be common. Given the difficulty of predicting or measuring entropic and enthalpic changes to useful precision, or using this information in design, we recommend ligand engineering efforts instead focus on computational and experimental methodologies to directly assess changes in binding free energy.

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Figures

Figure 1
Figure 1. Entropy-enthalpy compensation as a general phenomenon in thermodynamics
Three examples of compensating entropic and enthalpic contributions to the free energy as a function of temperature in general thermodynamic phenomena. The free energy (ΔG) of the process as a function of temperature is shown, along with enthalpic (ΔH) and entropic (TΔS) contributions.(a) transfer of neopentane from neat phase to water (data from Fig. 3 of Ref. [40]);(b) myoglobin unfolding (data from Table 2 of Ref. [41]).(c) protein association (data from Fig. 3b of Ref. [35]). In all three cases, ΔH andTΔS change substantially while ΔG remains almost constant, suggesting substantial entropy-enthalpy compensation.
Figure 2
Figure 2. Examples of severe compensation reported in the calorimetry literature
Several cases where ligand modifications lead to large changes in the enthalpic and entropic contributions to binding while the overall binding free energy remains essentially unchanged.(a) Severe compensation in HIV-1 protease inhibitors (data from Table 1 of Ref. [11]);(b) para-substituted benzamidinium trypsin inhibitors binding to trypsin (data from Table 1 of Ref. [14]);(b) nonpolar ring expansions in arylsulfonamide trypsin inhibitors (data from Table S3 of Ref. [8]). Quantities in parentheses denote one standard error of last significant digit.
Figure 3
Figure 3. Compensation behavior in calorimetry data
All plots showapparent compensation behavior between enthalpic (ΔH) and entropic (TΔS) components of free energy of binding.(a) Apparent compensation behavior from ITC measurements of Ca2+ to calcium-binding proteins (black circles) with linear fit (red dashed line, slope = 0.92(5),R2 = 0.96(3) by bootstrap) (data from Fig. 3 of Ref. [48]);(b) Meta-analysis of ITC measurements of protein-ligand complexes (black circles) selected from the BindingDB database [12] with linear fit (red dashed line, slope = 0.93(3),R2 = 0.91(2)) (data from Fig. 1 of Ref. [13]);(c) Independent ITC measurements performed in different laboratories usingidentical samples of ligand ligand (CBS binding to bovine carbonic anhydrase II) from the ABRF-MIRG’02 assessment [49] shows apparent (but fallacious) compensation over a wide range of energies, and error bars (representing one standard error) much smaller than the actual variation among independent measurements (computed from Table 3 of Ref. [49]). Horizontal and vertical bars denotereported measurement errors, which significantly underestimate the true inter-experiment variation. Linear fit denoted by red dashed line (slope=0.99(2),R2 = 0.997(1)).(d) Instrumental limitations on binding affinities measurable by ITC restrict the measurable range of ΔG (but not ΔH) to the unshaded region, inducing a linear correlation in ΔH andTΔS due to the “window effect” (data from Fig. 1 of Ref. [5]).
Figure 4
Figure 4. Distribution of published binding free energies and correlation with enthalpy
(a) Distribution of binding free energies computed from ChEMBL pKi activity data (data from Fig. 4 of Ref. [50]);(b) Poor correlation of enthalpy (ΔH) with free energy (ΔG) of binding from meta-analysis of ITC measurements [13] selected from the BindingDB database [12] (data from Fig. 2a of Ref. [13]). While aldose reductase (red squares) and HIV-1 protease (blue triangles) show some correlation between enthalpy and free energy of binding, correlation is generally poor for other complexes, and enthalpies span a much broader range than free energies.
Figure 5
Figure 5. Typical ITC experimental configuration and data
(a) A typical experimental configuration for power-compensating isothermal titration calorimetry (ITC).(b) Typical data from an ITC experiment showing applied power as a function of time (top) and integrated heats of injection with fit to thermodynamic parameters (bottom) (reproduced with permission from Fig. 2 of [35]).
Figure 6
Figure 6. Simple model system illustrating weak entropy-enthalpy compensation
An idealized protein and ligand interact via a Morse potential that is strengthened or weakened to simulate ligand modifications.(a) Intermolecular Morse potentialU(r) =De[1−e−a(r−r0)]2, withr0 = 2.8 Å,a = 1/(0.5 Å), and well depthDe varying from 2–10 kcal/mol.(b) Potential of mean forceF(r) =U(r)−kBT ln4πr2 between protein and ligand as a function of intermolecular distancer for temperatureT = 25 C.(c) Standard entropic (TΔS) and enthalpic (ΔH) contributions to the binding free energy for different well depthsDe, computed from classical statistical mechanics. Note that, while some entropy-enthalpy compensation is apparent, it is not linear.
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