On the binding affinity of macromolecular interactions: daring to ask why proteins interact.
On the binding affinity of macromolecular interactions: daring to ask why proteins interact.
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DOI：
10.1098/rsif.2012.0835
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发表时间：
2013-02
期刊：
影响因子：
--
通讯作者：
Bonvin AM
中科院分区：
文献类型：
--
作者：
Kastritis PL;Bonvin AM
蛋白质之间的相互作用是以精确和时间依赖的方式进行的，是细胞功能的基础。结合亲和力，定义为这些相互作用的强度，被转化为解离常数（Kd）中的物理化学术语，后者是确定是否在溶液中形成相互作用的实验测量。由于其在药物开发中的基础作用，从结构模型预测结合亲和力已经是40多年来的活跃研究问题。然而，所有可用的方法都不能单独从坐标预测蛋白质-蛋白质复合物的结合亲和力。在这里，我们研究了理论和实验的限制，复杂的结构亲和关系的推导。到目前为止，大多数工作都集中在二元相互作用上。越来越复杂的系统还远未被理解。与结合亲和力相关的主要物理化学测量是掩埋表面积，但它不适用于柔性复合物。对于后者，必须有一个显着的熵的贡献，将不得不在未来近似。我们预见，这些相互作用的任何理论建模将不得不遵循一个综合的方法，考虑生物学，化学和物理基础蛋白质-蛋白质识别。
Interactions between proteins are orchestrated in a precise and time-dependent manner, underlying cellular function. The binding affinity, defined as the strength of these interactions, is translated into physico-chemical terms in the dissociation constant (Kd), the latter being an experimental measure that determines whether an interaction will be formed in solution or not. Predicting binding affinity from structural models has been a matter of active research for more than 40 years because of its fundamental role in drug development. However, all available approaches are incapable of predicting the binding affinity of protein–protein complexes from coordinates alone. Here, we examine both theoretical and experimental limitations that complicate the derivation of structure–affinity relationships. Most work so far has concentrated on binary interactions. Systems of increased complexity are far from being understood. The main physico-chemical measure that relates to binding affinity is the buried surface area, but it does not hold for flexible complexes. For the latter, there must be a significant entropic contribution that will have to be approximated in the future. We foresee that any theoretical modelling of these interactions will have to follow an integrative approach considering the biology, chemistry and physics that underlie protein–protein recognition.
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