PDF(Pubmed)
Abstract：
We introduce a novel tree-based method for visualizing molecular conformation sampling. Our method offers enhanced precision in highlighting conformational differences and facilitates the observation of local minimas within proteins fold space. The projection of empirical laboratory data on the tree allows us to create a link between protein conformations and disease relevant data. To demonstrate the efficacy of our approach, we applied it to the ATP-binding cassette subfamily D member 1 (ABCD1) transporter responsible for very long-chain fatty acids (VLCFAs) import into peroxisomes. The genetic disorder called X-linked adrenoleukodystrophy (XALD) is characterized by the accumulation of VLCFA due to pathogenic variants in the ABCD1 gene. Using in silico molecular simulation, we examined the behavior of 16 prevalent mutations alongside the wild-type protein, exploring both inward and outward open forms of the transporter through molecular simulations. We evaluated from resulting trajectories the energy potential related to the ABCD1 interactions with ATP molecules. We categorized XALD patients based on the severity and progression of their disease, providing a unique clinical perspective. By integrating this data into our numerical framework, our study aimed to uncover the molecular underpinnings of XALD, offering new insights into disease progression. As we explored molecular trajectories and conformations resulting from our study, the tree-based method not only contributes valuable insights into XALD but also lays a solid foundation for forthcoming drug design studies. We advocate for the broader adoption of our innovative approach, proposing it as a valuable tool for researchers engaged in molecular simulation studies.
摘要：
我们介绍了一种新颖的基于树的方法来可视化分子构象采样。我们的方法在突出构象差异方面提供了增强的精度，并有助于观察蛋白质折叠空间内的局部最小值。实验实验室数据在树上的投影使我们能够在蛋白质构象和疾病相关数据之间建立联系。为了证明我们方法的有效性，我们将其应用于负责超长链脂肪酸(VLCFAs)导入过氧化物酶体的ATP结合盒亚家族D成员1(ABCD1)转运蛋白。称为X连锁肾上腺脑白质营养不良（XALD）的遗传性疾病的特征在于由于ABCD1基因中的致病变体而导致的VLCFA的积累。使用计算机分子模拟，我们检查了16种流行突变与野生型蛋白的行为，通过分子模拟探索转运蛋白的向内和向外开放形式。我们从所得轨迹评估了与ABCD1与ATP分子相互作用相关的能量势。我们根据疾病的严重程度和进展对XALD患者进行分类，提供独特的临床视角。通过将这些数据整合到我们的数值框架中，我们的研究旨在揭示XALD的分子基础，提供对疾病进展的新见解。当我们探索由我们的研究产生的分子轨迹和构象时，基于树的方法不仅为XALD提供了宝贵的见解，而且为即将进行的药物设计研究奠定了坚实的基础。我们主张更广泛地采用我们的创新方法，提出将其作为从事分子模拟研究的研究人员的有价值的工具。
