Entropy-Enthalpy Compensation: Role and Ramifications in Biomolecular Ligand Recognition and Design

Abstract

Recent calorimetric studies of small molecule interactions with 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 while 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.

Intrinsically disordered chromatin protein NUPR1 binds to the C-terminal region of Polycomb RING1B

“…Second, we did not observe two transitions, or alternatively a very broad one, in the far-UV CD thermal denaturations (which could indicate the presence of two well-folded proteins that are dissociating). Finally, we could argue that the flexibility of the formed complex, where NUPR1 is not folded, was responsible for the absence of thermogram in ITC (37). The persistently disordered conformation of NUPR1 seems to be a general feature (33,34,38): Whatever molecule (synthetic, DNA, or protein) is bound to it, it is not capable of altering its disordered nature.…”

“…First, we tried isothermal titration calorimetry (ITC) experiments at several pH values above 7.0 between wild-type NUPR1 and C-RING1B; in all conditions explored we did not observe a bindingassociated heat signal. Because we observed binding by using other techniques (discussed below), the absence of thermogram in ITC could be due to (i) a low affinity due to a high flexibility in the complex (36,37) or (ii) a very small amount of heat exchange with the environment. Based on our results (discussed below), we suggest that the most plausible explanation is the latter.…”

Collaborative routes to clarifying the murky waters of aqueous supramolecular chemistry

“…However, there are issues with the accuracy and hence utility of large portions of it. 76,77 In terms of the sheer quantity, ΔG(K a ) data dominates: ΔG(K a ) > ΔH ≈ ΔS ≫ ΔC p ≫ ΔV. This situation is a reflection of the dominance of spectroscopy and the ease by which it yields K a .…”

“…77 Relatedly, there is considerable debate about enthalpy-entropy compensation (EEC) and about the relevance of the slope of linear regression of ΔS-ΔH plots. As has been recently reviewed, 76 EEC may be due to handling and correlated errors, window effects (instrumentation limitations, data selection bias, and publication bias), or indeed may have a physical basis such as solvent reorganization and conformational restriction. There is no clear understanding of the root cause(s) of EEC, and there is considerable latent chemical space here for the two communities to collaboratively address this void.…”

Determinação da afinidade e assinatura termodinâmica de inibidores da cruzaína por calorimetria de titulação isotérmica

“…Ao mesmo tempo, o ligante e certos grupos na proteína perdem liberdade conformacional (redução de graus de liberdade) resultando em uma mudança desfavorável na entropia. 59 Existem três situações distintas para os ligantes:…”