Human Health Therapeutics Research Centre, National Research Council Canada, 6100 Royalmount Avenue, Montreal, QC, H4P 2R2, Canada.
Institute of Parasitology, McGill University, 21111 Lakeshore Road, Sainte-Anne-de-Bellevue, QC, H9X 3V9, Canada.
Sci Rep. 2023 Sep 13;13(1):15107. doi: 10.1038/s41598-023-42090-5.
Predicting the structure of antibody-antigen complexes has tremendous value in biomedical research but unfortunately suffers from a poor performance in real-life applications. AlphaFold2 (AF2) has provided renewed hope for improvements in the field of protein-protein docking but has shown limited success against antibody-antigen complexes due to the lack of co-evolutionary constraints. In this study, we used physics-based protein docking methods for building decoy sets consisting of low-energy docking solutions that were either geometrically close to the native structure (positives) or not (negatives). The docking models were then fed into AF2 to assess their confidence with a novel composite score based on normalized pLDDT and pTMscore metrics after AF2 structural refinement. We show benefits of the AF2 composite score for rescoring docking poses both in terms of (1) classification of positives/negatives and of (2) success rates with particular emphasis on early enrichment. Docking models of at least medium quality present in the decoy set, but not necessarily highly ranked by docking methods, benefitted most from AF2 rescoring by experiencing large advances towards the top of the reranked list of models. These improvements, obtained without any calibration or novel methodologies, led to a notable level of performance in antibody-antigen unbound docking that was never achieved previously.
预测抗体-抗原复合物的结构在生物医学研究中具有巨大的价值，但在实际应用中表现不佳。AlphaFold2（AF2）为蛋白质-蛋白质对接领域的改进提供了新的希望，但由于缺乏共同进化的限制，对抗体-抗原复合物的效果有限。在这项研究中，我们使用基于物理的蛋白质对接方法构建诱饵集，其中包含低能量对接解决方案，这些解决方案在几何上接近天然结构（阳性）或不接近（阴性）。然后将对接模型输入到 AF2 中，使用基于归一化 pLDDT 和 pTMscore 指标的新复合评分来评估它们的置信度，该评分是在 AF2 结构细化之后得出的。我们展示了 AF2 复合评分在重新评分对接构象方面的优势，既可以（1）对阳性/阴性进行分类，也可以（2）特别强调早期富集时的成功率。诱饵集中至少存在中等质量的对接模型，但不一定是对接方法排名很高的模型，从 AF2 重新评分中获益最多，它们在重新排序的模型列表中排名上升幅度很大。这些改进是在没有任何校准或新方法的情况下获得的，使得在未结合的抗体-抗原对接方面取得了以前从未达到过的显著性能水平。
