Miller D W, Dill K A
Graduate Group in Biophysics, University of California at San Francisco 94143-1204, USA.
Protein Sci. 1997 Oct;6(10):2166-79. doi: 10.1002/pro.5560061011.
Models of ligand binding are often based on four assumptions: (1) steric fit: that binding is determined mainly by shape complementarity; (2) native binding: that ligands mainly bind to native states; (3) locality: that ligands perturb protein structures mainly at the binding site; and (4) continuity: that small changes in ligand or protein structure lead to small changes in binding affinity. Using a generalization of the 2D HP lattice model, we study ligand binding and explore these assumptions. We first validate the model by showing that it reproduces typical binding behaviors. We observe ligand-induced denaturation, ANS and heme-like binding, and "lock-and-key" and "induced-fit" specific binding behaviors characterized by Michaelis-Menten or more cooperative types of binding isotherms. We then explore cases where the model predicts violations of the standard assumptions. For example, very different binding modes can result from two ligands of identical shape. Ligands can sometimes bind highly denatured states more tightly than native states and yet have Michaelis-Menten isotherms. Even low-population binding to denatured states can cause changes in global stability, hydrogen-exchange rates, and thermal B-factors, contrary to expectations, but in agreement with experiments. We conclude that ligand binding, similar to protein folding, may be better described in terms of energy landscapes than in terms of simpler mass-action models.
（1）空间契合：即结合主要由形状互补性决定；（2）天然结合：即配体主要与天然状态结合；（3）局部性：即配体主要在结合位点干扰蛋白质结构；（4）连续性：即配体或蛋白质结构的微小变化导致结合亲和力的微小变化。使用二维HP晶格模型的一种推广，我们研究配体结合并探索这些假设。我们首先通过证明它能重现典型的结合行为来验证该模型。我们观察到配体诱导的变性、ANS和类血红素结合，以及以米氏或更具协同性的结合等温线为特征的“锁钥”和“诱导契合”特异性结合行为。然后，我们探索模型预测违反标准假设的情况。例如，形状相同的两种配体可能导致非常不同的结合模式。配体有时与高度变性状态的结合比与天然状态的结合更紧密，但仍具有米氏等温线。甚至与变性状态的低丰度结合也会导致全局稳定性、氢交换率和热B因子的变化，这与预期相反，但与实验结果一致。我们得出结论，与蛋白质折叠类似，配体结合用能量景观来描述可能比用更简单的质量作用模型更好。
