title: Mechanism of Mcl-1 Conformational Regulation Upon Small Molecule Binding Revealed by Molecular Dynamic Simulation.
abstract: 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 (ΔEvdw ) and non-polar solvation energy (ΔGnp ) 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(BH) (3) 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(BH) (3) complex is improved beyond its direct binding affinity toward Mcl-1 itself, and compound 3 exhibits much more efficiency to compete with Puma(BH) (3) than compound 2. Our study provides a new strategy to improve inhibitory activity on Mcl-1 based on the conformational dynamic change.
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, 116024, China.|School of Innovation Experiment, Dalian University of Technology, Dalian, 116024, China.
authors.forename: Anhui
authors.initials: A
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, 116024, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Song
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, 116024, China.
authors.forename: Ziqian
authors.initials: Z
authors.lastname: Wang
authors.affiliation: School of Life Science and Medicine, Dalian University of Technology, Panjin, 124221, China.
authors.forename: Yubo
authors.initials: Y
authors.lastname: Liu
authors.affiliation: School of Life Science and Technology, Dalian University of Technology, Dalian, 116024, China.
authors.forename: Yudan
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Engineering Mechanics, Dalian University of Technology, Dalian, 116024, China.
authors.forename: Yahui
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, 116024, China.
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D056004:Molecular Dynamics Simulation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000737:chemistry*; D011487:Protein Conformation
chemical_list: C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein
keywords: Mcl-1; binding free energy; conformation change; inhibitor; molecular dynamics simulation