Molecular dynamics study of segment peptides of Bax, Bim, and Mcl-1 BH3 domain of the apoptosis-regulating proteins bound to the anti-apoptotic Mcl-1 protein

Abstract

Mcl-1 has emerged as a potential therapeutic target in the treatment of several malignancies. Peptides representing BH3 region of pro-apoptotic proteins have been shown to bind the hydrophobic cleft of anti-apoptotic Mcl-1 and this segment is responsible for modulating the apoptotic pathways in living cells. Understanding the molecular basis of protein-peptide interaction is required to develop potent inhibitors specific for Mcl-1. Molecular dynamics simulations were performed for Mcl-1 in complex with three different BH3 peptides derived from Mcl-1, Bax, and Bim. Accordingly, the calculated binding free energies using MM-PBSA method are obtained and comparison with the experimentally determined binding free energies is made. The interactions involving two conserved charged residues (Aspi, and Arg/Lysi-4) and three upstream conserved hydrophobic residues (Leui-5, Ile/Vali-2, and Glyi-1, respectively) of BH3 peptides play the important roles in the structural stability of the complexes. The calculated results exhibit that the interactions of Bim BH3 peptides to Mcl-1 is stronger than the complex with Bax 19BH3 peptides. The hydrophobic residues (position i - 9, i - 8 and i + 2) of BH3 peptides can be involved in their inhibitory specificity. The calculated results can be used for designing more effective MCL-1 inhibitors.

Toward Understanding Mcl-1 Promiscuous and Specific Binding Mode

“…Fluctuation values in helical parts did not exceed 1.5 Å (Figure S2 in the Supporting Information (SI)). In some complexes, an enhancement of α-helicity for the peptide ligands was observed, which is a phenomenon already described in MD simulations by Zhao et al In the four complexes, the most important flexibilities for Mcl-1 were observed in N and C-terminal parts and in the loop between α1 and α2 helices (Figure S2), in the same manner as in the simulations on Mcl-1/Bim, Mcl-1/Bax, and Mcl-1/Mcl-1 BH3 peptide complexes by Zhao and co-workers but not in the Mcl-1/Bim simulations published by Yang et al where this loop was omitted in simulations. Our fluctuations analysis showed, once more, agreement with the Zhao’s results, with similarly elevated Mcl-1 flexibility in loop α3−α4.…”

“…Our fluctuations analysis showed, once more, agreement with the Zhao’s results, with similarly elevated Mcl-1 flexibility in loop α3−α4. Zhao et al proposed that the fluctuations in this loop are related to the structural adjustment of Mcl-1 α4 helix with different BH3 peptides . Nevertheless, the flexibility of this loop and of the α4−α5 loop was different in the Mcl-1/Bad complex.…”

Molecular dynamics exploration of the binding mechanism and properties of single-walled carbon nanotube to WT and mutant VP35 FBP region of Ebola virus

“…To analyze the effect of the mutants on the binding affinity, the binding free energy decomposition was used to decompose the binding free energy into energy per residue, which could be summed over an atom group to obtain different energy contributions coming from the residues side-chain and backbone by the MM-GB/SA method [39][40][41] in the AMBER12 module. Quantitative information about binding free energy decomposition is significantly useful for the located key residues that contribute to the ligand and protein binding.…”

Exploration micromechanism of VP35 IID interaction and recognition dsRNA: A molecular dynamics simulation

“…The standard AMBER force field (ff99SB) was used as the parameters for all the simulations. Each system was solvated in the truncated octahedron periodic box of the TIP3P water modes with a cutoff 12 Å. An appropriate number of Na + or Cl − counterions were added to neutralize the negative or positive charge of the system.…”