个人信息Personal Information
教授
博士生导师
硕士生导师
性别:女
毕业院校:大连理工大学
学位:博士
所在单位:医学部
学科:化学生物学. 药理学. 细胞生物学
办公地点:Chemical complex building,D513
联系方式:zczhang@dlut.edu.cn 13942696903
电子邮箱:zczhang@dlut.edu.cn
Mechanism of Mcl-1 Conformational Regulation Upon Small Molecule Binding Revealed by Molecular Dynamic Simulation
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论文类型:期刊论文
发表时间:2016-04-01
发表刊物:CHEMICAL BIOLOGY & DRUG DESIGN
收录刊物:SCIE、PubMed、Scopus
卷号:87
期号:4
页面范围:551-561
ISSN号:1747-0277
关键字:binding free energy; conformation change; inhibitor; Mcl-1; molecular dynamics simulation
摘要:Inhibition of interactions between Mcl-1 and proapoptotic proteins is considered to be a therapeutic strategy to induce apoptosis in cancer cells. Here, we adopted molecular dynamics simulation with molecular mechanics-Poisson Boltzmann/surface area method (MM-PB/SA) to study the inhibition mechanism of three Mcl-1 inhibitors, compounds 1, 2 and 3. Analysis of energy components shows that the better binding free energy of compound 3 than compounds 1 and 2 is attributable to the van der Waals energy (E-vdw) and non-polar solvation energy (G(np)) upon binding. In addition to the excellent agreement with previous experimentally determined affinities, our simulation results further show a bend of helix 4 on Mcl-1 upon compound 3 binding, which is driven by hydrophobic interaction with residue Val(253), leading to a narrowed BH3-binding groove to impede Puma(BH3) binding. The computational result is consistent with our competitive isothermal titration calorimetry (ITC) assays, which shows that the competitive ability of compound 3 toward Mcl-1/Puma(BH3) complex is improved beyond its direct binding affinity toward Mcl-1 itself, and compound 3 exhibits much more efficiency to compete with Puma(BH3) than compound 2. Our study provides a new strategy to improve inhibitory activity on Mcl-1 based on the conformational dynamic change.