Graduate Group in Biophysics, Department of Pharmaceutical Chemistry, University of California, San Francisco, California, USA.
Proteins. 2011 Mar;79(3):821-9. doi: 10.1002/prot.22920. Epub 2010 Dec 6.
Prior studies suggest that antibody affinity maturation is achieved, in part, via prearranging the CDRs for binding. The implication is that the entropy cost of binding is reduced and that this rigidification occurs as a consequence of somatic mutations during maturation. However, how these mutations modulate CDR flexibility is unclear. Here, molecular dynamics simulations captured CDR flexibility differences between four mature antibodies (7G12, AZ28, 28B4, and 48G7) and their germline predecessors. Analysis of their trajectories: (1) rationalized how mutations during affinity maturation restrict CDR motility, (2) captured the equilibrium between bound and unbound conformations for the H3 loop of unliganded 7G12, and (3) predicted a set of new mutations that, according to our simulations, should diminish binding by increasing flexibility.
先前的研究表明，抗体亲和力成熟部分是通过预先安排 CDR 来实现结合的。这意味着结合的熵成本降低了，并且这种僵化是由于成熟过程中的体细胞突变而发生的。然而，这些突变如何调节 CDR 的灵活性尚不清楚。在这里，分子动力学模拟捕捉到了四个成熟抗体（7G12、AZ28、28B4 和 48G7）与其原始种系之间 CDR 灵活性的差异。对它们轨迹的分析：(1) 合理地解释了亲和力成熟过程中的突变如何限制 CDR 的运动性，(2) 捕捉到了未结合的 7G12 的 H3 环在结合和未结合构象之间的平衡，(3) 根据我们的模拟预测了一组新的突变，这些突变应该通过增加灵活性来降低结合。
