GPIbα-VWF复合物突变的热稳定性和结合能分析

Purpose: The GPIbα-A1 interaction mediates the crucial initial step of multistep platelet adhesion process from stop bleeding to maintain hemostasis on disrupted vessel wall at sites of injury. Structure variations in A1 of VWF can induce to the blocking or accelerating platelet adhesion and aggregation, resulting in venous thrombotic and bleeding disorders. The aim of this study is to reveal the influence of A1 variations in GPIbα-A1 interaction for more clear understanding on the vascular physiology and pathogenesis of diverse thrombosis, and von Willebrand disease. Methods:The techniques of virtual mutation and molecular dynamic simulation, and the softwares of Discovery Studio and NAMD were used in this study. The stability and binding energy of GPIbα-VWF complex were measured under different A1 mutations. Results: 1) Natural mutation tends to select stable mutation. Possibility of Cysteine and Isoleucine to induced mutation is higher than other amino acids. 2) The binding affinity of GPIbα-A1 in mutation state is stronger than wide type A1 state, the same situation in Type 2B mutation state. 3) There are negative correlation between the binding energy of A1 mutation with pH values under physiological pH range. Conclusion: The data in this study, may offer some new therapeutic approaches to inhibiting pathological platelet adhesion during thrombosis and/or intervention to the bleeding disorder VWD.