用能量偏好优化生成更真实多样的蛋白质构象,替代耗时的分子模拟。
EPO: Diverse and Realistic Protein Ensemble Generation via Energy Preference Optimization
- 通过随机微分方程采样结合能量排序机制,实现无需额外模拟的高效构象探索。
- 在四肽、ATLAS和快速折叠基准上,9项评估指标达新最优,构象多样且物理合理。
- 适用于结构生物学与药物发现,特别适合已有预训练模型的快速增强。
准确探索蛋白质构象集合对揭示功能至关重要,但分子动力学(MD)模拟因计算成本高和势垒困住问题而困难重重。本文提出能量偏好优化(EPO),一种在线精炼算法,可将预训练的蛋白质构象生成器转化为能量感知采样器,无需额外的MD轨迹。EPO利用随机微分方程采样探索构象空间,并引入基于列表级偏好优化的新能量排序机制。关键在于,EPO设计了一个实用的上界,用于高效近似连续时间生成模型中长轨迹的不可计算概率,使其可轻松适配现有预训练生成器。在四肽、ATLAS和快速折叠基准上,EPO成功生成了多样化且物理真实的构象集合,在九项评估指标上达到新最优。结果表明,仅凭能量偏好信号即可有效引导生成模型获得热力学一致的构象集合,为长期MD模拟提供替代方案,并拓展了学习势能在结构生物学和药物发现中的应用。
原文摘要 · Abstract (English)
Accurate exploration of protein conformational ensembles is essential for uncovering function but remains hard because molecular-dynamics (MD) simulations suffer from high computational costs and energy-barrier trapping. This paper presents Energy Preference Optimization (EPO), an online refinement algorithm that turns a pretrained protein ensemble generator into an energy-aware sampler without extra MD trajectories. Specifically, EPO leverages stochastic differential equation sampling to explore the conformational landscape and incorporates a novel energy-ranking mechanism based on list-wise preference optimization. Crucially, EPO introduces a practical upper bound to efficiently approximate the intractable probability of long sampling trajectories in continuous-time generative models, making it easily adaptable to existing pretrained generators. On Tetrapeptides, ATLAS, and Fast-Folding benchmarks, EPO successfully generates diverse and physically realistic ensembles, establishing a new state-of-the-art in nine evaluation metrics. These results demonstrate that energy-only preference signals can efficiently steer generative models toward thermodynamically consistent conformational ensembles, providing an alternative to long MD simulations and widening the applicability of learned potentials in structural biology and drug discovery.
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