Jahan Ishrat, Nayeem Shahid M
Department of Chemistry, Aligarh Muslim University Aligarh-202002 U.P. India
RSC Adv. 2020 Jul 30;10(46):27598-27614. doi: 10.1039/d0ra02151b. eCollection 2020 Jul 21.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by the misfolding of Cu, Zn superoxide dismutase (SOD1). Several earlier studies have shown that monomeric apo SOD1 undergoes significant local unfolding dynamics and is the predecessor for aggregation. Here, we have employed atomistic molecular dynamics (MD) simulations to study the structure and dynamics of monomeric apo and holo SOD1 in water, aqueous urea and aqueous urea-TMAO (trimethylamine oxide) solutions. Loop IV (zinc-binding loop) and loop VII (electrostatic loop) of holo SOD1 are considered as functionally important loops as they are responsible for the structural stability of holo SOD1. We found larger local unfolding of loop IV and VII of apo SOD1 as compared to holo SOD1 in water. Urea induced more unfolding in holo SOD1 than apo SOD1, whereas the stabilization of both the form of SOD1 was observed in ternary solution ( water/urea/TMAO solution) but the extent of stabilization was higher in holo SOD1 than apo SOD1. The partially unfolded structures of apo SOD1 in water, urea and holo SOD1 in urea were identified by the exposure of the hydrophobic cores, which are highly dynamic and these may be the initial events of aggregation in SOD1. Our simulation studies support the formation of aggregates by means of the local unfolding of monomeric apo SOD1 as compared to holo SOD1 in water.
肌萎缩侧索硬化症（ALS）是一种由铜锌超氧化物歧化酶（SOD1）错误折叠引起的进行性神经退行性疾病。早期的几项研究表明，单体脱辅基SOD1经历了显著的局部去折叠动力学过程，是聚集的前身。在这里，我们采用原子分子动力学（MD）模拟来研究单体脱辅基和全酶SOD1在水、尿素水溶液和尿素 - 三甲胺氧化物（TMAO）水溶液中的结构和动力学。全酶SOD1的环IV（锌结合环）和环VII（静电环）被认为是功能重要的环，因为它们负责全酶SOD1的结构稳定性。我们发现，与水中的全酶SOD1相比，脱辅基SOD1的环IV和环VII有更大程度的局部去折叠。尿素诱导全酶SOD1的去折叠比脱辅基SOD1更多，而在三元溶液（水/尿素/TMAO溶液）中观察到两种形式的SOD1都得到了稳定，但全酶SOD1的稳定程度高于脱辅基SOD1。通过疏水核心的暴露确定了水中脱辅基SOD1和尿素中全酶SOD1的部分去折叠结构，这些结构高度动态，可能是SOD1聚集的初始事件。我们的模拟研究支持了与水中的全酶SOD1相比，单体脱辅基SOD1通过局部去折叠形成聚集体的观点。
