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

Molecular Dynamics Simulations of Interactional Mechanism and Binding Energy Calculations between Kinase ABL and Small Molecules Binding at Myristoyl Pocket

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.自山能计算结果表明,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αl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.

We performed molecular dynamics simulations on complexes of ABL to investigate the binding of imatinib, P16 （binding at the ATP pocket）, and ST J, 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 ST J, 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 al-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.