4.3 Article

VH-VL interdomain dynamics observed by computer simulations and NMR

期刊

出版社

WILEY
DOI: 10.1002/prot.25872

关键词

antibodies; molecular dynamics simulations; NMR; V-H and V-L domain orientation

资金

  1. Austrian Science Fund [P30565, P30737]

向作者/读者索取更多资源

The relative orientation of the two variable domains, V-H and V-L, influences the shape of the antigen binding site, that is, the paratope, and is essential to understand antigen specificity. ABangle characterizes the V-H-V-L orientation by using five angles and a distance and compares it to other known structures. Molecular dynamics simulations of antibody variable domains (Fvs) reveal fluctuations in the relative domain orientations. The observed dynamics between these domains are confirmed by NMR experiments on a single-chain variable fragment antibody (scFv) in complex with IL-1 beta and an antigen-binding fragment (Fab). The variability of these relative domain orientations can be interpreted as a structural feature of antibodies, which increases the antibody repertoire significantly and can enlarge the number of possible binding partners substantially. The movements of the V-H and V-L domains are well sampled with molecular dynamics simulations and are in agreement with the NMR ensemble. Fast Fourier transformation of the ABangle metrics allows to assign timescales of 0.1-10 GHz to the fastest collective interdomain movements. The results clearly show the necessity of dynamics to understand and characterize the favorable orientations of the V-H and V-L domains implying a considerable binding interface flexibility and reveal in all antibody fragments (Fab, scFv, and Fv) very similar V-H-V-L interdomain variations comparable to the distributions observed for known X-ray structures of antibodies. Significance Statement Antibodies have become key players as therapeutic agents. The binding ability of antibodies is determined by the antigen-binding fragment (Fab), in particular the variable fragment region (Fv). Antigen-binding is mediated by the complementarity-determining regions consisting of six loops, each three of the heavy and light chain variable domain V-H and V-L. The relative orientation of the V-H and V-L domains influences the shape of the antigen-binding site and is a major objective in antibody design. In agreement with NMR experiments and molecular dynamics simulations, we show a considerable binding site flexibility in the low nanosecond timescale. Thus we suggest that this flexibility and its implications for binding and specificity should be considered when designing and optimizing therapeutic antibodies.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.3
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据