通过优化嵌入空间,实现蛋白质结构生成的稳定高效控制。
Robust Inference-Time Steering of Protein Diffusion Models via Embedding Optimization
- 用嵌入优化替代坐标扰动,改变模型先验以匹配实验约束。
- 在稀疏距离约束下性能相当,在冷冻电镜图谱拟合中更优。
- 对超参数不敏感,减少扩散步数仍保持高精度,适合实际应用。
结构生物物理的核心挑战是生成既符合物理规律又与实验数据一致的生物分子构象。尽管序列到结构的扩散模型提供了强大先验,但后验采样方法通过实验似然梯度扰动原子坐标进行引导。然而,当目标位于先验低密度区域时,需大幅提高似然权重,导致采样不稳定且对超参数敏感。我们提出EmbedOpt,一种推理时引导框架,引入正交优化轴:不固定先验进行后验采样,而是直接优化模型的条件嵌入。该嵌入空间编码丰富的共进化信号,优化它可使结构先验与实验约束对齐。实验证明,EmbedOpt在稀疏距离约束下达到与坐标基后验采样相当的性能,在冷冻电镜图谱拟合(包括真实噪声数据)中表现更优。此外,其平滑优化行为使其对超参数具有鲁棒性,跨两个数量级变化仍稳定,且减少扩散步数后仍保持良好性能。代码已开源:https://github.com/rs-station/embedopt。
原文摘要 · Abstract (English)
A core challenge in structural biophysics is generating biomolecular conformations that are both physically plausible and consistent with experimental measurements. While sequence-to-structure diffusion models provide powerful priors, posterior sampling methods steer generation by perturbing atomic coordinates with gradients from experimental likelihoods. However, when the target lies in a low-density region of the prior, these methods require aggressive upweighting of the likelihood that can destabilize sampling and be sensitive to hyperparameters. We propose EmbedOpt, an inference-time steering framework that introduces an orthogonal optimization axis: rather than performing posterior sampling under a fixed prior, EmbedOpt directly optimizes the prior by updating the model's conditional embedding. This embedding space encodes rich coevolutionary signals, so optimizing it shifts the structural prior to align with experimental constraints. Empirically, EmbedOpt matches coordinate-based posterior sampling baselines on sparse distance constraints and outperforms them on cryo-electron microscopy map fitting, including real, noisy experimental ones. Furthermore, EmbedOpt's smooth optimization behavior yields robustness to hyperparameters spanning two orders of magnitude and enables comparable performance with fewer diffusion steps. Code is available at https://github.com/rs-station/embedopt.
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