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Mechanism of Mcl‐1 Conformational Regulation Upon Small Molecule Binding Revealed by Molecular Dynamic Simulation
Author(s) -
Wang Anhui,
Song Ting,
Wang Ziqian,
Liu Yubo,
Fan Yudan,
Zhang Yahui,
Zhang Zhichao
Publication year - 2016
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12679
Subject(s) - isothermal titration calorimetry , chemistry , molecular dynamics , molecular mechanics , van der waals force , puma , hydrophobic effect , molecule , solvation , binding site , binding energy , stereochemistry , cooperative binding , small molecule , computational chemistry , biochemistry , organic chemistry , physics , nuclear physics , gene
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 (ΔE vdw ) and non‐polar solvation energy (ΔG 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 BH 3‐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.