Molecular dynamic simulation to explore the molecular basis of Btk-PH domain interaction with Ins(1,3,4,5)P4.
Molecular dynamic simulation to explore the molecular basis of Btk-PH domain interaction with Ins(1,3,4,5)P4.
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分子动力学模拟探索 Btk-PH 结构域与 Ins(1,3,4,5)P4 相互作用的分子基础
DOI：
10.1155/2013/580456
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发表时间：
2013
影响因子：
--
通讯作者：
Hu G
中科院分区：
文献类型：
--
作者：
Lu D;Jiang J;Liang Z;Sun M;Luo C;Shen B;Hu G
布鲁顿酪氨酸激酶含有一个普列克底物蛋白同源结构域，它特异性结合肌醇1，3，4，5-四磷酸（Ins（1，3，4，5）P4），其参与B细胞的成熟。本文研究了12个系统，包括野生型和11个突变体，K12 R，S14 F，K19 E，R28 C/H，E41 K，L11 P，F25 S，Y 40 N，和K12 R-R28 C/H，以研究每个突变体的配体结合位点的变化。结合分子力学/Poisson-Boltzmann溶剂可及表面积方法的分子动力学模拟已被应用到12个系统，并已获得合理的突变体结构和它们的结合自由能作为最终分类的标准。结果，K12 R、K19 E、R28 C/H和E41 K突变体这五种结构被归类为“功能突变”，而L11 P、S14 F、F25 S和Y 40 N被归类为“折叠突变”。这种对每个突变体的结合亲和力及其分类的严格研究为Btk-PH结构域的生物学功能和相关突变引起的疾病提供了一些新的见解。
Bruton's tyrosine kinase contains a pleckstrin homology domain, and it specifically binds inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4), which is involved in the maturation of B cells. In this paper, we studied 12 systems including the wild type and 11 mutants, K12R, S14F, K19E, R28C/H, E41K, L11P, F25S, Y40N, and K12R-R28C/H, to investigate any change in the ligand binding site of each mutant. Molecular dynamics simulations combined with the method of molecular mechanics/Poisson-Boltzmann solvent-accessible surface area have been applied to the twelve systems, and reasonable mutant structures and their binding free energies have been obtained as criteria in the final classification. As a result, five structures, K12R, K19E, R28C/H, and E41K mutants, were classified as “functional mutations,” whereas L11P, S14F, F25S, and Y40N were grouped into “folding mutations.” This rigorous study of the binding affinity of each of the mutants and their classification provides some new insights into the biological function of the Btk-PH domain and related mutation-causing diseases.
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