Lee F S, Chu Z T, Bolger M B, Warshel A
Department of Chemistry, University of Southern California, Los Angeles 90089-1062.
Protein Eng. 1992 Apr;5(3):215-28. doi: 10.1093/protein/5.3.215.
The study of antibody-antigen interactions should greatly benefit from the development of quantitative models for the evaluation of binding free energies in proteins. The present work addresses this challenge by considering the test case of the binding free energies of phosphorylcholine analogs to the murine myeloma protein McPC603. This includes the evaluation of the differential binding energy as well as the absolute binding energies and their corresponding electrostatic contributions. Four different approaches are examined: the Protein Dipoles Langevin Dipoles (PDLD) method, the semi-microscopic PDLD (PDLD/S) method, a free energy perturbation (FEP) method based on an adiabatic charging procedure and a linear response approximation that accelerates the FEP calculation. The PDLD electrostatic calculations are augmented by estimates of the relevant hydrophobic and steric contributions. The determination of the hydrophobic energy involves an approach which considers the modification of the effective surface area of the solute by local field effects. The steric contributions are analyzed in terms of the corresponding reorganization energies. This treatment, which considers the protein as a harmonic system, views the steric forces as the restoring forces for the electrostatic interactions. The FEP method is found to give unreliable results with regular cut-off radii and starts to give quantitative results only in very expensive treatment with very large cut-off radii. The PDLD and PDLD/S methods are much faster than the FEP approach and give reasonable results for both the relative and absolute binding energies. The speed and simplicity of the PDLD/S method make it an effective strategy for interactive docking studies and indeed such an option is incorporated in the program MOLARIS. A component analysis of the different energy contributions of the FEP treatment and a similar PDLD analysis indicate that electrostatic effects provide the largest contribution to the differential binding energy, while the hydrophobic and steric contributions are much smaller. This finding lends further support to the idea that electrostatic interactions play a major role in determining the antigen specificity of McPC603.
抗体 - 抗原相互作用的研究应能从用于评估蛋白质中结合自由能的定量模型的发展中受益匪浅。本研究通过考虑磷酰胆碱类似物与鼠骨髓瘤蛋白McPC603的结合自由能这一测试案例来应对这一挑战。这包括对差分结合能以及绝对结合能及其相应静电贡献的评估。研究了四种不同的方法：蛋白质偶极朗之万偶极（PDLD）方法、半微观PDLD（PDLD/S）方法、基于绝热充电程序和加速FEP计算的线性响应近似的自由能微扰（FEP）方法。通过估计相关的疏水和空间贡献来增强PDLD静电计算。疏水能量的确定涉及一种考虑溶质有效表面积因局部场效应而改变的方法。从相应的重组能角度分析空间贡献。这种将蛋白质视为谐波系统的处理方法，将空间力视为静电相互作用的恢复力。发现FEP方法在常规截止半径下给出不可靠的结果，只有在使用非常大的截止半径进行非常昂贵的处理时才开始给出定量结果。PDLD和PDLD/S方法比FEP方法快得多，并且对于相对和绝对结合能都给出合理的结果。PDLD/S方法的速度和简便性使其成为交互式对接研究的有效策略，实际上程序MOLARIS中就包含这样一个选项。对FEP处理的不同能量贡献的成分分析以及类似的PDLD分析表明，静电效应在差分结合能中贡献最大，而疏水和空间贡献要小得多。这一发现进一步支持了静电相互作用在决定McPC603的抗原特异性中起主要作用的观点。
