激酶ABL与肉豆蔻酰位点小分子作用机理的分子动力学模拟及自由能计算

摘要

We performed molecular dynamics simulations on complexes of ABL to investigate the binding of imatinib, P16 (binding at the ATP pocket), and STJ, MS7, MS9, 3YY, and MYR (binding at the myristoyl pocket). The calculated binding energies were then decomposed to determine the ligand-residue pair interactions, using the generalized Born surface area (GBSA) method. The results showed that the binding energies are almost the same for STJ, MS7, and MS9, and their absolute values are larger than those of 3YY and MYR. The decomposition of the binding energy revealed that three residues (ILE502, VAL506, and LEU510) contribute significantly to hold the αI-helix in a bent conformation in the STJ-ABL and MYR-ABL complexes. The root mean square deviation (RMSD) values for the residues forming myristoyl pocket showed that the inhibitors in this pocket decrease the flexibility of the corresponding residues.%　　采用分子动力学方法研究激酶 ABL 与 ATP 位点小分子 imatinib、P16及变构位点小分子 STJ、MS7、MS9、3YY、MYR 等的结合，并用 GBSA (generalized Born surface area)方法将结合自由能分解到各残基。自由能计算结果表明，小分子 STJ、MS7、MS9有利于 imatinib 与 ABL 结合；小分子 STJ、MS7、MS9与激酶 ABL的结合自由能接近，绝对值均大于 ABL 与3YY、MYR 的结合自由能。能量分解表明， ABL 残基 ILE502、VAL506、LEU510与STJ和MYR的相互作用是αI螺旋处于弯曲状态的重要原因。模拟过程中ABL肉豆蔻酰口袋残基均方根偏差(RMSD)变化值表明， STJ等小分子抑制剂与ABL结合后降低了肉豆蔻酰口袋残基的柔性。