Department of Chemistry, Bar Ilan University , Ramat-Gan 52900, Israel.
J Chem Inf Model. 2015 Nov 23;55(11):2349-64. doi: 10.1021/acs.jcim.5b00312. Epub 2015 Oct 29.
Cystic Fibrosis (CF) is a lethal, genetic disease caused by mutations to the CFTR chloride channel. The most common CF causing mutation is the deletion of F508 from the first Nucleotide Binding Domain (F508del-NBD1). This mutation leads to a thermally unstable domain and a misfolded, nonfunctioning CFTR. Replica Exchange MD simulations were used to simulate seven NBD1 constructs including wt and F508del-NBD1 both alone and in the presence of known rescuing mutations as well as F508del-NBD1 in complex with a known small (ligand) stabilizer. Analyzing the resulting trajectories suggests that differences in the biochemical properties of the constructs result from local and coupled differences in their dynamic profiles. A comparative analysis of these profiles as well as of the resulting trajectories reveals how the different perturbations exert their deleterious, rescuing, and stabilizing effects on NBD1. These simulations may therefore be useful for the design and mechanism-of-action analysis of new NBD1 stabilizers.
囊性纤维化（CF）是一种致命的遗传性疾病，由 CFTR 氯离子通道的突变引起。最常见的 CF 致病突变是第一个核苷酸结合域（NBD1）中 F508 的缺失（F508del-NBD1）。这种突变导致热不稳定域和错误折叠、无功能的 CFTR。复制交换 MD 模拟用于模拟七个 NBD1 结构，包括 wt 和 F508del-NBD1 单独存在和存在已知的挽救突变，以及与已知小分子（配体）稳定剂结合的 F508del-NBD1。分析所得轨迹表明，结构的生化特性的差异源于其动态特性的局部和耦合差异。对这些谱以及所得轨迹的比较分析揭示了不同的扰动如何对 NBD1 产生有害、挽救和稳定作用。因此，这些模拟可能有助于新的 NBD1 稳定剂的设计和作用机制分析。
