Fakhoury Ziad, Sosso Gabriele C, Habershon Scott
Department of Chemistry, University of Warwick, Coventry CV4 7AL, U.K.
J Chem Theory Comput. 2024 Sep 4;20(18):8340-53. doi: 10.1021/acs.jctc.4c00878.
We have recently shown how physically realizable protein-folding pathways can be generated using directed walks in the space of inter-residue contact-maps; combined with a back-transformation to move from protein contact-maps to Cartesian coordinates, we have demonstrated how this approach can generate protein-folding trajectory ensembles without recourse to molecular dynamics. In this article, we demonstrate that this framework can be used to study a challenging protein-folding problem that is known to exhibit two different folding paths which were previously identified through molecular dynamics simulation at several different temperatures. From the viewpoint of protein-folding mechanism prediction, this particular problem is extremely challenging to address, specifically involving folding to an identical nontrivial compact native structure along distinct pathways defined by heterogeneous secondary structural elements. Here, we show how our previously reported contact-map-based protein-folding strategy can be significantly enhanced to enable accurate and robust prediction of heterogeneous folding paths by (i) introducing a novel topologically informed metric for comparing two protein contact maps, (ii) reformulating our graph-represented folding path generation, and (iii) introducing a new and more reliable structural back-mapping algorithm. These changes improve the reliability of generating structurally sound folding intermediates and dramatically decrease the number of physically irrelevant folding intermediates generated by our previous simulation strategy. Most importantly, we demonstrate how our enhanced folding algorithm can successfully identify the alternative folding mechanisms of a multifolding-pathway protein, in line with direct molecular dynamics simulations.
我们最近展示了如何通过在残基间接触图空间中进行定向游走生成物理上可实现的蛋白质折叠途径；结合从蛋白质接触图到笛卡尔坐标的反向变换，我们证明了这种方法如何能够在不借助分子动力学的情况下生成蛋白质折叠轨迹集合。在本文中，我们证明了这个框架可用于研究一个具有挑战性的蛋白质折叠问题，该问题已知表现出两条不同的折叠路径，这两条路径先前是通过在几个不同温度下的分子动力学模拟确定的。从蛋白质折叠机制预测的角度来看，这个特定问题极难解决，具体涉及沿着由异质二级结构元件定义的不同路径折叠成相同的非平凡紧密天然结构。在这里，我们展示了如何通过以下方式显著增强我们先前报道的基于接触图的蛋白质折叠策略，以实现对异质折叠路径的准确且稳健的预测：（i）引入一种用于比较两个蛋白质接触图的新颖拓扑信息度量；（ii）重新制定我们以图表示的折叠路径生成方法；（iii）引入一种新的、更可靠的结构反向映射算法。这些改变提高了生成结构合理的折叠中间体的可靠性，并显著减少了我们先前模拟策略生成的物理上不相关的折叠中间体的数量。最重要的是，我们展示了我们增强的折叠算法如何能够成功识别多折叠路径蛋白质的替代折叠机制，这与直接分子动力学模拟结果一致。
