Abstract：
Pycnodysostosis is an atypical autosomal recessive condition of Lysosomal storage disorder that originated due to the deficit of the enzyme Cathepsin K which is vital for normal osteoclast action in bone resorption. Abnormal degradation of type 1 collagen and accumulation of toxic undigested collagen fibers in lysosomes of the osteoclast cells resulting in high bone density, brittle bones, and a short stature is caused in CTSK protein-carrying individuals. The broad aim of this study is to identify the most significant variant through various computational pipelines. This study was initiated by retrieving a total number of thirty-six variants from NCBI, HGMD, and UniProt databases, and the Y283C variant was found to be more significant by various standard computational tools. A structural investigation was performed to understand and gain a better knowledge about the interaction profile for the native (1BY8) and variant (Y283C) with Relacatib (a small-molecule drug that blocks the function of Cathepsin K, an enzyme that has been linked to osteoporosis, osteoarthritis, and other bone-degrading diseases). The interaction profile was analyzed using molecular docking. Relacatib (ligand) had an average binding affinity for both native (-7.16 kcal/mol) and Y283C (-6.76 kcal/mol). Finally, Molecular dynamics simulations were done in duplicates to recognize the variant (Y283C) activity of the protein structure against Relacatib for 100 ns. This study assists in comprehending the most pathogenic amino-acid variant, the ligand interaction with the protein structure, and paves the way for understanding the steadiness of the ligand with the native and selected significant amino-acid variant.Communicated by Ramaswamy H. Sarma.
摘要：
胆裂症是溶酶体贮积症的一种非典型常染色体隐性遗传疾病，起源于组织蛋白酶K的缺乏，该酶对骨吸收中的正常破骨细胞作用至关重要。1型胶原的异常降解和有毒的未消化胶原纤维在破骨细胞的溶酶体中的积累导致高骨密度,脆骨,在携带CTSK蛋白的个体中引起身材矮小。这项研究的广泛目的是通过各种计算管道确定最重要的变体。这项研究是通过从NCBI中检索到总共36种变体而开始的，HGMD,和UniProt数据库，Y283C变体被各种标准计算工具发现更重要。进行了结构研究，以了解和更好地了解天然（1BY8）和变体（Y283C）与Relacatib（一种小分子药物，可阻断组织蛋白酶K的功能，一种与骨质疏松症有关的酶，骨关节炎,和其他骨骼降解疾病)。使用分子对接分析相互作用曲线。Relacatib(配体)对天然(-7.16kcal/mol)和Y283C(-6.76kcal/mol)具有平均结合亲和力。最后,重复进行分子动力学模拟以识别蛋白质结构针对Relacatib的变体(Y283C)活性100ns。这项研究有助于理解最具致病性的氨基酸变异，配体与蛋白质结构的相互作用，并为理解配体与天然和选定的重要氨基酸变体的稳定性铺平了道路。由RamaswamyH.Sarma沟通。
