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Exploring designability of electrostatic complementarity at an antigen-antibody interface directed by mutagenesis biophysical analysis and molecular dynamics simulations

机译：探索通过诱变生物物理分析和分子动力学模拟指导的抗原-抗体界面上的静电互补性的可设计性

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摘要

Antibodies protect organisms from a huge variety of foreign antigens. Antibody diversity originates from both genetic and structural levels. Antigen recognition relies on complementarity between antigen-antibody interfaces. Recent methodological advances in structural biology and the accompanying rapid increase of the number of crystal structures of proteins have enabled atomic-level manipulation of protein structures to effect alterations in function. In this study, we explored the designability of electrostatic complementarity at an antigen-antibody interface on the basis of a crystal structure of the complex. We designed several variants with altered charged residues at the interface and characterized the designed variants by surface plasmon resonance, circular dichroism, differential scanning calorimetry, and molecular dynamics simulations. Both successes and failures of the structure-based design are discussed. The variants that compensate electrostatic interactions can restore the interface complementarity, enabling the cognate antigen-antibody binding. Retrospectively, we also show that these mutational effects could be predicted by the simulations. Our study demonstrates the importance of charged residues on the physical properties of this antigen-antibody interaction and suggests that computational approaches can facilitate design of antibodies that recognize a weakly immunogenic antigen.
机译：抗体可以保护生物免受各种外来抗原的侵害。抗体的多样性源自遗传和结构水平。抗原识别依赖于抗原-抗体界面之间的互补性。结构生物学的最新方法学进展以及随之而来的蛋白质晶体结构数量的迅速增加，使得对蛋白质结构进行原子级操纵以实现功能改变。在这项研究中，我们基于复合物的晶体结构，探索了抗原-抗体界面上静电互补的可设计性。我们设计了几种在界面处带有带电残基的变体，并通过表面等离振子共振，圆二色性，差示扫描量热法和分子动力学模拟对设计的变体进行了表征。讨论了基于结构的设计的成功与失败。补偿静电相互作用的变体可以恢复界面互补性，从而实现相关抗原-抗体结合。回顾性地，我们还表明，这些突变效应可以通过模拟预测。我们的研究证明了带电荷残基对这种抗原-抗体相互作用的物理性质的重要性，并表明计算方法可以促进识别弱免疫原性抗原的抗体的设计。

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