arXiv:2412.09420cs.LG2024-12NeurIPS被引 4

用神经场混合建模蛋白复合物的构象与组成异质性,提升冷冻电镜重建精度。

Mixture of neural fields for heterogeneous reconstruction in cryo-EM

  • 将结构建模为K个神经场的混合,从头推断构象与组成
  • 在含高构象变异性的人工数据上实现精准重建
  • 适用于复杂样品,如细胞裂解液中的多蛋白混合物

冷冻电镜(cryo-EM)是一种在近生理环境下成像大分子集合的实验技术。尽管近期进展实现了单个生物分子复合物动态构象的重建,现有方法仍难以有效建模具有构象与组成异质性的样本。特别是包含多种蛋白质混合的数据集,需要联合推断结构、姿态、组分类别和构象状态以完成三维重建。本文提出Hydra方法,通过参数化结构为来自K个神经场之一,实现构象与组成异质性的完全从头建模。采用新的基于似然的损失函数,在由具有高度构象可变性的蛋白质混合组成的合成数据集上验证了该方法的有效性。此外,我们在一个包含多种蛋白复合物的细胞裂解液实验数据集上展示了Hydra的应用效果。Hydra扩展了异质重建方法的表达能力,从而拓宽了冷冻电镜对更复杂样本的应用范围。

原文摘要 · Abstract (English)

Cryo-electron microscopy (cryo-EM) is an experimental technique for protein structure determination that images an ensemble of macromolecules in near-physiological contexts. While recent advances enable the reconstruction of dynamic conformations of a single biomolecular complex, current methods do not adequately model samples with mixed conformational and compositional heterogeneity. In particular, datasets containing mixtures of multiple proteins require the joint inference of structure, pose, compositional class, and conformational states for 3D reconstruction. Here, we present Hydra, an approach that models both conformational and compositional heterogeneity fully ab initio by parameterizing structures as arising from one of K neural fields. We employ a new likelihood-based loss function and demonstrate the effectiveness of our approach on synthetic datasets composed of mixtures of proteins with large degrees of conformational variability. We additionally demonstrate Hydra on an experimental dataset of a cellular lysate containing a mixture of different protein complexes. Hydra expands the expressivity of heterogeneous reconstruction methods and thus broadens the scope of cryo-EM to increasingly complex samples.

冷冻电镜神经场异质重建蛋白质结构

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