Department of Microbiology, Shivaji University, Kolhapur 416004, Maharashtra (M.S.), India.
Comput Biol Med. 2013 Dec;43(12):2063-70. doi: 10.1016/j.compbiomed.2013.09.021. Epub 2013 Oct 8.
Cysteine protease is known to degrade amyloid beta peptide which is a causative agent of Alzheimer's disease. This cleavage mechanism has not been studied in detail at the atomic level. Hence, a three-dimensional structure of cysteine protease from Xanthomonas campestris was constructed by homology modeling using Geno3D, SWISS-MODEL, and MODELLER 9v7. All the predicted models were analyzed by PROCHECK and PROSA. Three-dimensional model of cysteine protease built by MODELLER 9v7 shows similarity with human cathepsin B crystal structure. This model was then used further for docking and simulation studies. The molecular docking study revealed that Cys17, His87, and Gln88 residues of cysteine protease form an active site pocket similar to human cathepsin B. Then the docked complex was refined by molecular dynamic simulation to confirm its stable behavior over the entire simulation period. The molecular docking and MD simulation studies showed that the sulfhydryl hydrogen atom of Cys17 of cysteine protease interacts with carboxylic oxygen of Lys16 of Aβ peptide indicating the cleavage site. Thus, the cysteine protease model from X. campestris having similarity with human cathepsin B crystal structure may be used as an alternate approach to cleave Aβ peptide a causative agent of Alzheimer's disease.
半胱氨酸蛋白酶已知可降解淀粉样β肽，该肽是阿尔茨海默病的致病因子。这种切割机制尚未在原子水平上进行详细研究。因此，使用 Geno3D、SWISS-MODEL 和 MODELLER 9v7 通过同源建模构建了黄单胞菌胱氨酸蛋白酶的三维结构。所有预测的模型均通过 PROCHECK 和 PROSA 进行分析。由 MODELLER 9v7 构建的胱氨酸蛋白酶的三维模型与人类组织蛋白酶 B 的晶体结构具有相似性。然后，该模型进一步用于对接和模拟研究。分子对接研究表明，胱氨酸蛋白酶的 Cys17、His87 和 Gln88 残基形成与人类组织蛋白酶 B 相似的活性口袋。然后通过分子动力学模拟对对接复合物进行优化，以确认其在整个模拟过程中的稳定行为。分子对接和 MD 模拟研究表明，胱氨酸蛋白酶的 Cys17 的巯基氢原子与 Aβ肽的 Lys16 的羧酸氧相互作用，表明切割位点。因此，与人类组织蛋白酶 B 晶体结构具有相似性的黄单胞菌胱氨酸蛋白酶模型可作为切割阿尔茨海默病致病因子 Aβ肽的替代方法。
