Title: Resolving Tangling in Multi-Conformer Refinement via Iterative Projections Show Chinese title

Title: 通过迭代投影解决多构象精修中的纠缠问题

Abstract: The advent of advanced crystallographic techniques has shifted structural biology from static, single-conformer models toward probing protein dynamics. Extracting cooperative motions from temporally and spatially averaged electron density maps requires both high-resolution data and refinement algorithms capable of handling conformational heterogeneity. However, current refinement protocols often fail due to the tangling phenomenon, in which conformational states become improperly intertwined during optimization. Here, we present an automated refinement methodology based on iterative projections within the divide-and-concur framework. This approach enables seamless integration of geometric constraints with experimental density constraints derived from observed scattering amplitudes. By allowing each atom to satisfy density constraints independently, we show that this framework effectively circumvents tangling artifacts and achieves robust refinement performance, even for models initialized with R-factors as high as 12%. Just as iterative projections revolutionized phase retrieval in crystallography, we demonstrate that they can also address the optimization challenges in multi-conformational refinement. This work establishes a computational foundation for advancing crystallographic methodologies to resolve conformational heterogeneity and ultimately capture protein dynamics at atomic resolution. Show Chinese abstract

Abstract: 先进的晶体学技术的出现使结构生物学从静态的单一构象模型转向研究蛋白质动力学。 从时间上和空间上平均的电子密度图中提取协同运动需要高分辨率数据以及能够处理构象异质性的精修算法。 然而，当前的精修协议常常由于纠缠现象而失败，其中在优化过程中构象状态被不恰当地交织在一起。 在此，我们提出了一种基于分而治之框架内的迭代投影的自动化精修方法。 这种方法能够将几何约束与从观测散射振幅中获得的实验密度约束无缝集成。 通过允许每个原子独立满足密度约束，我们表明该框架可以有效避免纠缠伪影，并实现稳健的精修性能，即使对于初始R因子高达12%的模型也是如此。 正如迭代投影在晶体学中革新了相位检索一样，我们证明它们也可以解决多构象精修中的优化挑战。 这项工作为推进晶体学方法以解决构象异质性并最终在原子分辨率下捕捉蛋白质动力学奠定了计算基础。