Vajda S, Weng Z, Rosenfeld R, DeLisi C
Department of Biomedical Engineering, Boston University, Massachusetts 02215.
Biochemistry. 1994 Nov 29;33(47):13977-88. doi: 10.1021/bi00251a004.
A coherent framework is presented for determining the free energy change accompanying ligand binding to protein receptors. The most important new feature of the method is the contribution of the flexibility of the free ligand, and hence its conformational change on binding, to the free energy. Flexibility introduces two additional terms in the free energy difference: the internal energy difference between the ligand in the bound and free states and the backbone entropy loss. The former requires taking explicit account of the difference in solvation of the various forms of the free ligand. The solvation free energy change is estimated using an atomic solvation parameter model [Eisenberg & Mclachlan (1986) Nature 319, 199-203], with an improved parameter set. In order to evaluate the method, we applied it to three data sets for which increasingly general methods are required. The set to which the most restrictive theory can be applied consists of eight crystallized endopeptidase--protein inhibitor complexes which do not change conformation on binding and for which the major contribution to the solvation free energy is entropic. The results are in good agreement with the measured values and somewhat better than those previously reported in the literature. The second data set compares the relative binding free energies of biotin and its analogs for streptavidin. In this case the structures are also rigid, but solvation free energy must include both enthalpic and entropic components. We find that differential free energy predictions are approximately the same as those obtained by free energy perturbation techniques. The final application is an analysis of the measured stabilities of 13 different MHC receptor-peptide complexes. In this case we show that flexibility contributes 30-50% of the free energy change and find a correlation of 0.88 between our predicted free energies and peptide dissociation times.
本文提出了一个连贯的框架，用于确定配体与蛋白质受体结合时伴随的自由能变化。该方法最重要的新特点是自由配体的灵活性对自由能的贡献，以及因此其结合时的构象变化。灵活性在自由能差中引入了两个额外的项：结合态和自由态配体之间的内能差以及主链熵损失。前者需要明确考虑自由配体各种形式的溶剂化差异。使用原子溶剂化参数模型[艾森伯格和麦克拉克伦（1986年）《自然》319卷，199 - 203页]，并采用改进的参数集来估计溶剂化自由能变化。为了评估该方法，我们将其应用于三个数据集，对于这些数据集需要越来越通用的方法。最严格理论可适用的数据集由八个结晶的内肽酶 - 蛋白质抑制剂复合物组成，它们在结合时不会改变构象，并且对溶剂化自由能的主要贡献是熵。结果与测量值高度吻合，并且比文献中先前报道的结果稍好。第二个数据集比较了生物素及其类似物与链霉亲和素的相对结合自由能。在这种情况下，结构也是刚性的，但溶剂化自由能必须包括焓和熵成分。我们发现差分自由能预测与通过自由能微扰技术获得的预测大致相同。最后的应用是对13种不同的MHC受体 - 肽复合物的测量稳定性进行分析。在这种情况下，我们表明灵活性对自由能变化的贡献为30 - 50%，并且我们预测的自由能与肽解离时间之间的相关性为0.88。
