用多模态令牌编码抗体环结构,提升设计与预测精度。
Tokenizing Loops of Antibodies
- 基于二面角和序列训练对比学习模型,生成抗体环的紧凑令牌。
- 检索相似H3环结构准确率提升5.9%,覆盖所有抗体环类型。
- 可嵌入语言模型,助力抗体亲和力预测与逆向折叠生成。
抗体互补决定区(CDR)是环状结构,对识别抗原至关重要,也是新生物药设计的关键。自1980年代起,将CDR结构分类为典型簇的方法帮助识别了关键结构特征,但现有方法覆盖有限,难以融入蛋白质基础模型。本文提出免疫球蛋白环分词器Igloo,一种融合主链二面角与序列信息的多模态抗体环分词器。Igloo采用对比学习目标,使具有相似二面角的环在潜在空间中更接近。该模型能高效从结构数据库中检索最匹配的环结构,在识别H3环相似性上优于现有方法5.9%。Igloo为所有环分配令牌,解决典型簇覆盖不足问题,同时保留恢复典型构象的能力。为验证其通用性,我们构建IglooLM与IglooALM:前者在10个抗体-抗原靶标中,8个表现优于基础语言模型;性能与参数量7倍更高的先进模型相当。后者生成的抗体环在序列上更多样、结构上更一致,优于现有逆向折叠模型。Igloo展示了多模态令牌对抗体环多样性的建模优势,提升了蛋白质基础模型能力,推动了抗体CDR设计。
原文摘要 · Abstract (English)
The complementarity-determining regions of antibodies are loop structures that are key to their interactions with antigens, and of high importance to the design of novel biologics. Since the 1980s, categorizing the diversity of CDR structures into canonical clusters has enabled the identification of key structural motifs of antibodies. However, existing approaches have limited coverage and cannot be readily incorporated into protein foundation models. Here we introduce ImmunoGlobulin LOOp Tokenizer, Igloo, a multimodal antibody loop tokenizer that encodes backbone dihedral angles and sequence. Igloo is trained using a contrastive learning objective to map loops with similar backbone dihedral angles closer together in latent space. Igloo can efficiently retrieve the closest matching loop structures from a structural antibody database, outperforming existing methods on identifying similar H3 loops by 5.9\%. Igloo assigns tokens to all loops, addressing the limited coverage issue of canonical clusters, while retaining the ability to recover canonical loop conformations. To demonstrate the versatility of Igloo tokens, we show that they can be incorporated into protein language models with IglooLM and IglooALM. On predicting binding affinity of heavy chain variants, IglooLM outperforms the base protein language model on 8 out of 10 antibody-antigen targets. Additionally, it is on par with existing state-of-the-art sequence-based and multimodal protein language models, performing comparably to models with $7\times$ more parameters. IglooALM samples antibody loops which are diverse in sequence and more consistent in structure than state-of-the-art antibody inverse folding models. Igloo demonstrates the benefit of introducing multimodal tokens for antibody loops for encoding the diverse landscape of antibody loops, improving protein foundation models, and for antibody CDR design.
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