Dynamic Network Modelling of Bcl-2 Family Proteins
作者单位：上海有机化学研究所 State Key Laboratory of Bioorganic and Natural Products Chemistry Shanghai Institute of Organic Chemistry Chinese Academy of Sciences Department of Medicinal Chemistry School of Pharmacy Fudan University
会议名称：《2019中国化学会第十五届全国计算（机）化学学术会议》
会议日期：2019年
学科分类：1007[医学-药学(可授医学、理学学位)] 10[医学]
关 键 词：Bcl-2 Family Proteins Dynamic Network Inhibitors Multi-Target Drug
摘 要：The Bcl-2 family consists of several proteins that share Bcl-2 homology（BH） domain and control apoptosis by governing mitochondrial outer membrane permeabilization（MOMP）, which is a key step in the intrinsic pathway of apoptosis. However, the dynamic mechanism of action between the Bcl-2 family proteins is not clear. In addition, it remains an unknown issue that how small molecules induce apoptosis by regulating the protein-protein interaction network. Herein, we attempt to build a dynamic network model, which describes the interactions between the Bcl-2 family proteins by a set of ordinary differential equations. Two special nodes representing small molecules were added to our network model to investigate the induction of apoptosis by anti-apoptotic protein inhibitors. To fit the parameters of the model and verify its rationality, the Bcl-2 family proteins concentration was measured by quantitative western blotting assay. Interestingly, we have found some nonlinear dynamic properties in the dynamic network. When the concentration of the inhibitor is at a low level, the apoptosis signal（MOMP） value is nearly 0. Only the concentration exceeds a certain threshold, the apoptosis signal jump to a high level and the cell apoptosis is activated. This study has deepened our understanding on the Bcl-2 family protein interactions. By utilizing such a dynamic network model, it helps researchers to design the multi-target drugs or combination therapies.