用能量对齐优化抗体设计,生成更自然且结合力强的抗体。
Pareto-Optimal Energy Alignment for Designing Nature-Like Antibodies
- 三阶段训练框架:语言模型预训练+扩散模型联合优化+能量对齐
- 在多个能量目标下实现帕累托最优,提升抗体结合亲和力与合理性
- 支持在线数据迭代学习,适合生物制药领域抗体生成任务
我们提出一个三阶段深度学习框架,用于抗体序列-结构协同设计。首先利用数百万条抗体序列数据预训练语言模型;随后使用学习到的表示引导扩散模型,联合优化抗体的序列与结构;最后在对齐阶段,通过优化降低抗体与抗原结合位点的排斥力、提高吸引力,增强设计的合理性与功能性。为解决多能量目标间的冲突,我们将AbDPO扩展为多目标帕累托最优对齐方法。此外,采用带温度缩放的迭代学习范式,使模型能持续从多样在线数据中受益,无需额外数据。实验表明,该方法在生成帕累托前沿抗体方面优于基线与以往对齐技术,能高效产出高亲和力、类天然抗体。
原文摘要 · Abstract (English)
We present a three-stage framework for training deep learning models specializing in antibody sequence-structure co-design. We first pre-train a language model using millions of antibody sequence data. Then, we employ the learned representations to guide the training of a diffusion model for joint optimization over both sequence and structure of antibodies. During the final alignment stage, we optimize the model to favor antibodies with low repulsion and high attraction to the antigen binding site, enhancing the rationality and functionality of the designs. To mitigate conflicting energy preferences, we extend AbDPO (Antibody Direct Preference Optimization) to guide the model toward Pareto optimality under multiple energy-based alignment objectives. Furthermore, we adopt an iterative learning paradigm with temperature scaling, enabling the model to benefit from diverse online datasets without requiring additional data. In practice, our proposed methods achieve high stability and efficiency in producing a better Pareto front of antibody designs compared to top samples generated by baselines and previous alignment techniques. Through extensive experiments, we showcase the superior performance of our methods in generating nature-like antibodies with high binding affinity.
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