Chong L T, Duan Y, Wang L, Massova I, Kollman P A
Graduate Group in Biophysics, University of California, San Francisco, CA 94143-0446, USA.
Proc Natl Acad Sci U S A. 1999 Dec 7;96(25):14330-5. doi: 10.1073/pnas.96.25.14330.
We investigated the relative free energies of hapten binding to the germ line and mature forms of the 48G7 antibody Fab fragments by applying a continuum model to structures sampled from molecular dynamics simulations in explicit solvent. Reasonable absolute and very good relative free energies were obtained. As a result of nine somatic mutations that do not contact the hapten, the affinity-matured antibody binds the hapten >10(4) tighter than the germ line antibody. Energetic analysis reveals that van der Waals interactions and nonpolar contributions to solvation are similar and drive the formations of both the germ line and mature antibody-hapten complexes. Affinity maturation of the 48G7 antibody therefore appears to occur through reorganization of the combining site geometry in a manner that optimizes the balance of gaining favorable electrostatic interactions with the hapten and losing those with solvent during the binding process. As reflected by lower rms fluctuations in the antibody-hapten complex, the mature complex undergoes more restricted fluctuations than the germ line complex. The dramatically increased affinity of the 48G7 antibody over its germ line precursor is thus made possible by electrostatic optimization.
我们通过将连续介质模型应用于在明确溶剂中从分子动力学模拟采样得到的结构，研究了半抗原与48G7抗体Fab片段的胚系和成熟形式结合的相对自由能。得到了合理的绝对自由能和非常好的相对自由能。由于九个不与半抗原接触的体细胞突变，亲和力成熟的抗体结合半抗原的能力比胚系抗体强>10(4)倍。能量分析表明，范德华相互作用和对溶剂化的非极性贡献相似，并驱动胚系和成熟抗体-半抗原复合物的形成。因此，48G7抗体的亲和力成熟似乎是通过结合位点几何结构的重组实现的，这种重组方式优化了在结合过程中与半抗原获得有利静电相互作用和与溶剂失去这些相互作用之间的平衡。如抗体-半抗原复合物中较低的均方根波动所反映的，成熟复合物的波动比胚系复合物更受限制。因此，48G7抗体与其胚系前体相比亲和力的显著增加是通过静电优化实现的。
