Entropy-enthalpy compensation in solvation and ligand binding revisited
Entropy-enthalpy compensation in solvation and ligand binding revisited
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DOI：
10.1021/ja974061h
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发表时间：
1998-05-13
影响因子：
15
通讯作者：
Levy, RM
中科院分区：
文献类型：
--
作者：
Gallicchio, E;Kubo, MM;Levy, RM
本文讨论了熵焓补偿在溶剂化相对自由能和结合相对自由能研究中的作用，并讨论了文献中有关这一主题的一些问题。在这种情况下，相对自由能测量在涉及溶剂化或配体结合的热力学循环中由一个分子取代另一个分子所引起的自由能的变化。在这个过程中，分子之间的微观相互作用被有效地转化，产生了可测量的热力学性质的变化。这样的转换，当在计算机上通过自由能扰动模拟进行时，被称为“计算炼金术”。焓变测量的是分子间相互作用强度的变化，而熵变测量的是系统秩序的变化。然而，解释自由能的变化就比较困难了。事实上，对自由能变化的分析必然包括对相应的焓和熵变化的相对重要性的分析。5,6,13 -15熵焓补偿现象与我们的直觉一致，即分子之间更强的相互作用也会导致系统构型自由的减少，从而导致熵的减少。相应地，较弱的分子相互作用将产生较松散的分子结合和熵的增加。熵焓补偿的物理基础是如此直观明显，以至于这种现象有时被认为是热力学要求。特别是，设计分子优化性能的过程，如溶解度或配体结合的自由能，往往受到以下事实的阻碍：旨在加强溶质与溶剂的结合或配体与宿主的结合的变化，伴随着熵的补偿减少，导致自由能的微小变化（有时甚至不是预期的直接变化）
In this paper, we address the role of entropy-enthalpy compensation in the study of relative free energies of solvation and relative free energies of binding and address some issues regarding this subject in the literature. Relative free energy in this context measures the change in free energy caused by replacing one molecule with another during thermodynamic cycles involving either solvation or ligand binding. In this process, the microscopic interactions between the molecules are effectively transformed producing a measurable change of thermodynamic properties. Such transformations, when carried out on a computer by free energy perturbation simulations, have been dubbed “computational alchemy”. 8-12 The enthalpy change measures a change in the strength of the interactions between molecules while the entropy change measures a change in the order of the system. It is more difficult, however, to interpret free energy changes. Invariably, in fact, the analysis of free energy changes must involve the analysis of the relative importance of the corresponding enthalpy and entropy changes. 5, 6, 13-15The phenomenon of entropy-enthalpy compensation agrees with our intuition that a stronger interaction between molecules will also result in a reduction of the configurational freedom of the system and thus a reduction of the entropy. Correspondingly, weaker molecular interactions will produce a looser molecular association and an increase of the entropy. The physical basis for entropy-enthalpy compensation is so intuitively obvious that this phenomenon is sometimes considered to be a thermodynamic requirement. In particular, the process of designing molecules that optimize properties, such as solubility or free energy of ligand binding, is often impeded by the fact that changes directed to strengthen the association of the solute with the solvent, or the ligand to the host, are accompanied by a compensating reduction of the entropy, resulting in a small change in free energy (that sometimes is not even in the expected direc-