Froloff N, Windemuth A, Honig B
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA.
Protein Sci. 1997 Jun;6(6):1293-301. doi: 10.1002/pro.5560060617.
This paper describes a methodology to calculate the binding free energy (delta G) of a protein-ligand complex using a continuum model of the solvent. A formal thermodynamic cycle is used to decompose the binding free energy into electrostatic and non-electrostatic contributions. In this cycle, the reactants are discharged in water, associated as purely nonpolar entities, and the final complex is then recharged. The total electrostatic free energies of the protein, the ligand, and the complex in water are calculated with the finite difference Poisson-Boltzmann (FDPB) method. The nonpolar (hydrophobic) binding free energy is calculated using a free energy-surface area relationship, with a single alkane/water surface tension coefficient (gamma aw). The loss in backbone and side-chain configurational entropy upon binding is estimated and added to the electrostatic and the nonpolar components of delta G. The methodology is applied to the binding of the murine MHC class I protein H-2Kb with three distinct peptides, and to the human MHC class I protein HLA-A2 in complex with five different peptides. Despite significant differences in the amino acid sequences of the different peptides, the experimental binding free energy differences (delta delta Gexp) are quite small (< 0.3 and < 2.7 kcal/mol for the H-2Kb and HLA-A2 complexes, respectively). For each protein, the calculations are successful in reproducing a fairly small range of values for delta delta Gcalc (< 4.4 and < 5.2 kcal/mol, respectively) although the relative peptide binding affinities of H-2Kb and HLA-A2 are not reproduced. For all protein-peptide complexes that were treated, it was found that electrostatic interactions oppose binding whereas nonpolar interactions drive complex formation. The two types of interactions appear to be correlated in that larger nonpolar contributions to binding are generally opposed by increased electrostatic contributions favoring dissociation. The factors that drive the binding of peptides to MHC proteins are discussed in light of our results.
本文描述了一种使用溶剂连续介质模型计算蛋白质-配体复合物结合自由能（ΔG）的方法。一个形式化的热力学循环被用于将结合自由能分解为静电和非静电贡献。在这个循环中，反应物在水中解离，作为纯非极性实体缔合，然后最终复合物再带电。蛋白质、配体以及复合物在水中的总静电自由能使用有限差分泊松-玻尔兹曼（FDPB）方法计算。非极性（疏水）结合自由能使用自由能-表面积关系计算，采用单一的烷烃/水表面张力系数（γaw）。结合时主链和侧链构象熵的损失被估算并加到ΔG的静电和非极性组分上。该方法应用于小鼠MHC I类蛋白H-2Kb与三种不同肽段的结合，以及人类MHC I类蛋白HLA-A2与五种不同肽段的复合物。尽管不同肽段的氨基酸序列存在显著差异，但实验测得的结合自由能差异（ΔΔGexp）相当小（H-2Kb和HLA-A2复合物分别<0.3和<2.7 kcal/mol）。对于每种蛋白质，计算成功地重现了相当小范围的ΔΔGcalc值（分别<4.4和<5.2 kcal/mol），尽管H-2Kb和HLA-A2的相对肽段结合亲和力未被重现。对于所有处理的蛋白质-肽段复合物，发现静电相互作用阻碍结合，而非极性相互作用驱动复合物形成。这两种相互作用似乎是相关的，即对结合的较大非极性贡献通常被有利于解离的增加的静电贡献所抵消。根据我们的结果讨论了驱动肽段与MHC蛋白结合的因素。
