Stüve-Wiedemann 综合征 (SWS) 是一种罕见的常染色体隐性遗传疾病，其特征是体型矮小、细长的骨骼弯曲、手指弯曲、体温升高、呼吸困难或屏气期以及进食困难，尤其是原因婴儿死亡。 SWS 是白血病抑制因子受体基因中潜在错义突变的结果，反映为蛋白质水平上的大量氨基酸突变。采用计算机工具和技术，例如使用 Pred_MutHTP、I-Mutant2.0、PANTHER.db、PolyPhen 进行突变筛选，将突变分类为有害/破坏稳定，并结合实验数据分析，P136A 和 S279P 成为导致“效应”的突变。现有知识表明，SWS 进展是由构象改变和功能失调的 LIFR 实现的，无法与 LIF 结合并进一步形成 LIF/LIFR/gp130 信号复合物。为了深入了解所述突变对野生型蛋白质的影响，按照对接方法进行了全原子、显式、溶剂分子动力学模拟。因此，参考 RMSD、RMSF、蛋白质动态网络分析、能量景观图和结构域运动分析，发现未结合的 LIFR_WT 更容易像往常一样发生 LIF 结合，而突变体表现出相当大的结构域闭合以抑制 LIF 结合。我们通过 MM/GBSA 进行结合亲和力分析，并在 LIFR-LIF 对接后进行解离常数估计，发现与 SWS 相关的柔性突变体复合物相比，WT_complex 整体上更加稳定和紧凑。我们的研究提供了一种了解 LIFR 突变的分子水平影响的途径，这为治疗干预开辟了途径。版权所有 © 2024 Elsevier Ltd。保留所有权利。

Stüve-Wiedemann syndrome (SWS), a rare autosomal recessive disorder, characterized by diminutive size, curvature of the elongated bones, bent fingers, episodes of heightened body temperature, respiratory distress or periods of breath-holding, and challenges with feeding, especially causes fatality in infants. SWS is an outcome of potential missense mutations in the leukemia inhibitory factor receptor gene reflected as numerous amino acid mutations at protein level. Employing in silico tools and techniques like mutational screening with Pred_MutHTP, I-Mutant2.0, PANTHER.db, PolyPhen, to classify mutations as deleterious/destabilizing, in conjunction with experimental data analysis, P136A and S279P emerged as 'effect'-causing mutations. Pre-existing knowledge suggests, SWS progression is effectuated conformationally altered and dysfunctional LIFR, unable to bind to LIF and further form the LIF/LIFR/gp130 signalling complex. To gain functional insights into the effect of the said mutations on the wild type protein, an all-atom, explicit, solvent molecular dynamics simulation was performed following docking approaches. Consequently, referring to the RMSD, RMSF, protein dynamic network analysis, energy landscape plots and domain motion analysis, it was revealed that unbound LIFR_WT was more prone to LIF binding as usual whereas the mutants exhibited considerable domain closure to inhibit LIF binding. We conducted binding affinity analysis via MM/GBSA and dissociation constant estimation after LIFR-LIF docking and found the WT_complex to be more stable and compact as a whole when compared to the flexible mutant complexes thus being associated with SWS. Our study offers a route for understanding molecular level implications upon LIFR mutations which opens an avenue for therapeutic interventions.Copyright © 2024 Elsevier Ltd. All rights reserved.