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计算机模拟研究揭示了肌动蛋白结合蛋白 1 突变体的结构偏差，以及与肌萎缩侧索硬化症中利鲁唑和依达拉奉的相互作用。

In silico studies reveal structural deviations of mutant profilin-1 and interaction with riluzole and edaravone in amyotrophic lateral sclerosis.

机构信息

Department of Computer and Data Sciences, Faculty of Mathematical Sciences, Shahid Beheshti University, Tehran, Iran.

School of Biological Sciences, Institute for Research in Fundamental Sciences (IPM), 193955746, Tehran, Iran.

出版信息

Sci Rep. 2021 Mar 25;11(1):6849. doi: 10.1038/s41598-021-86211-4.

DOI:10.1038/s41598-021-86211-4
PMID:33767237
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7994392/
Abstract

This study aimed to investigate four of the eight PFN-1 mutations that are located near the actin-binding domain and determine the structural changes due to each mutant and unravel how these mutations alter protein structural behavior. Swapaa's command in UCSF chimera for generating mutations, FTMAP were employed and the data was analyzed by RMSD, RMSF graphs, Rg, hydrogen bonding analysis, and RRdisMaps utilizing Autodock4 and GROMACS. The functional changes and virtual screening, structural dynamics, and chemical bonding behavior changes, molecular docking simulation with two current FDA-approved drugs for ALS were investigated. The highest reduction and increase in Rg were found to exist in the G117V and M113T mutants, respectively. The RMSF data consistently shows changes nearby to this site. The in silico data described indicate that each of the mutations is capable of altering the structure of PFN-1 in vivo. The potential effect of riluzole and edaravone two FDA approved drugs for ALS, impacting the structural deviations and stabilization of the mutant PFN-1 is evaluated using in silico tools. Overall, the analysis of data collected reveals structural changes of mutant PFN-1 protein that may explain the neurotoxicity and the reason(s) for possible loss and gain of function of PFN-1 in the neurotoxic model of ALS.

摘要

本研究旨在研究位于肌动蛋白结合域附近的 PFN-1 突变中的四个突变，确定每个突变引起的结构变化，并揭示这些突变如何改变蛋白质的结构行为。我们使用 UCSF chimera 中的 Swapaa 命令生成突变，使用 FTMAP 进行分析，并利用 Autodock4 和 GROMACS 分析 RMSD、RMSF 图、Rg、氢键分析和 RRdisMaps。我们研究了功能变化和虚拟筛选、结构动力学以及与两种当前批准用于 ALS 的药物的化学结合行为变化的分子对接模拟。结果发现，G117V 和 M113T 突变体的 Rg 增加和减少最大。RMSF 数据一致显示该位点附近的变化。描述的计算数据表明，每种突变都能够改变 PFN-1 的结构。使用计算工具评估两种已批准用于 ALS 的药物——利鲁唑和依达拉奉对 PFN-1 突变体结构偏差和稳定性的潜在影响。总的来说，对收集到的数据进行分析揭示了突变 PFN-1 蛋白的结构变化，这可能解释了 ALS 神经毒性模型中 PFN-1 的神经毒性和功能可能丧失和获得的原因。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d56/7994392/f04b476ae8b9/41598_2021_86211_Fig12_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d56/7994392/5aed97e45c93/41598_2021_86211_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d56/7994392/72bc1c4025c6/41598_2021_86211_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d56/7994392/aa35a1bbc01a/41598_2021_86211_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d56/7994392/82dbb0e8ede0/41598_2021_86211_Fig10_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5d56/7994392/f04b476ae8b9/41598_2021_86211_Fig12_HTML.jpg

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