Abstract：
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.
摘要：
Stüve-Wiedemann综合征（SWS），一种罕见的常染色体隐性疾病,以尺寸小巧为特征，细长骨头的曲率，弯曲的手指，体温升高的事件，呼吸窘迫或屏气，以及喂养方面的挑战，尤其是导致婴儿死亡。SWS是白血病抑制因子受体基因中潜在错义突变的结果，反映为蛋白质水平的许多氨基酸突变。在计算机工具和技术中使用Pred_MutHTP进行突变筛选，I-Mutant2.0,PANTHER.db,PolyPhen,将突变归类为有害/不稳定，结合实验数据分析，P136A和S279P作为“效应”引起的突变出现。预先存在的知识表明，SWS进展是构象改变和功能失调的LIFR，无法与LIF结合并进一步形成LIF/LIFR/gp130信号传导复合物。为了获得对所述突变对野生型蛋白质的影响的功能见解，一个全原子,明确，溶剂分子动力学模拟是按照对接方法进行的。因此,提到RMSD，RMSF,蛋白质动态网络分析,能量景观地块和域运动分析，揭示了未结合的LIFR_WT像往常一样更倾向于LIF结合，而突变体表现出相当大的结构域封闭以抑制LIF结合。我们通过MM/GBSA进行了结合亲和力分析，并在LIFR-LIF对接后进行了解离常数估计，发现与与SWS相关的柔性突变复合物相比，WT_复合物整体上更稳定和紧凑。我们的研究为了解LIFR突变的分子水平含义提供了途径，这为治疗干预开辟了途径。
