Mechanism of Mcl-1 Conformational Regulation Upon Small Molecule Binding Revealed by Molecular Dynamic Simulation
发布时间：2019-03-13
点击次数：
- 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：
- Scopus、PubMed、SCIE
- 文献类型：
- J
- 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.
- 第一作者
- Wang, Anhui
- 合写作者
- Wang, Ziqian,Liu, Yubo,Fan, Yudan,Zhang, Yahui,Zhang, Zhichao,Song, Ting
- 通讯作者
- Zhang, ZC (reprint author), Dalian Univ Technol, Sch Chem, State Key Lab Fine Chem, Dalian 116024, Peoples R China.