![]() 18 Williams and coworkers suggested that residual motion in the complex will partly compensate for the loss in translational and rotational entropy, and that this residual motion will decrease as the strength of the complex is increased. In 1981, Jencks pointed out that in the association of two molecules, a favourable binding enthalpy has to overcome an unfavourable loss of translational and rotational entropy when two molecules form a complex, directly leading to EEC. ![]() 1,13–15 Owing to the importance of EEC for the understanding of molecular recognition and drug design, it has been thoroughly studied by both experimental and theoretical methods. 8–12 On the other hand, several examples where enthalpy and entropy enforce each other have also been reported. 1–3 Even if the EEC in some cases has been attributed to experimental errors and limitations 4,5 or to a natural consequence of thermodynamics, 1,6,7 there is now much clear evidence of EEC. The term has been used with several meanings, but recent reviews have clarified the concept. the binding of a drug candidate to a protein) is often to a large extent cancelled by a concurrent decrease in the entropy, is a much debated phenomenon. the observation that an increase in the enthalpy during the non-covalent association of two molecules ( e.g. Introduction The enthalpy–entropy compensation (EEC), i.e. However, if water molecules are added, the relation is blurred and it can be predicted that for a real binding reaction in water solution, both enthalpy–entropy compensation and anti-compensation can be observed, depending on the detailed interaction of the two molecules with water before and after binding, further complicated by dynamic effects. Thus, for homologous series of molecules with repeated interactions studied in vacuum, EEC is a rule. These relations often reflect the increasing size of the complexes coming from the translational and rotational entropies, but at least for the hydrogen-bonded complexes, it is significantly enhanced also by the vibrational entropy (which depends on the strength of the interaction). Within homologous series, linear relations between TΔ S and Δ H with slopes of 0.1–1.7 are obtained with no clear difference between dispersive or hydrogen-bonded systems (but ∼0.01 for ionic and covalent interactions). We see no qualitative difference between results obtained at the MM or QM level, and for all complexes except two very weak, EEC is observed, owing to the loss of translational and rotational entropy, typically counteracted by the vibrational entropy. Next, homologous series of complexes dominated either by dispersion or hydrogen bonds are studied. All three types of interactions give rise to EEC and a saturation of TΔ S as Δ H becomes strongly negative. We start with simple two-atom models, for which dispersion and electrostatics can be studied separately, showing that there is no fundamental difference between dispersion, electrostatics, or even covalent interactions. In this paper, enthalpy–entropy compensation (EEC) during the association of two molecules is studied by minimising model systems with molecular mechanics (MM) or quantum mechanics (QM), calculating translational, rotational, and vibrational contributions to the enthalpy and entropy with standard statistical-mechanics methods, using the rigid-rotor harmonic-oscillator approach.
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