TY - JOUR
T1 - Disruption of conserved polar interactions causes a sequential release of Bim mutants from the canonical binding groove of Mcl1
AU - Marimuthu, Parthiban
AU - Razzokov, Jamoliddin
AU - Eshonqulov, Gofur
N1 - begärrt fil (alg 4.2.2021) 12m, CC BY-NC-ND
PY - 2020/5/3
Y1 - 2020/5/3
N2 - Mcl1 is an important anti-apoptotic member of the Bcl2 family proteins that are upregulated in several cancer malignancies. The canonical binding groove (CBG) located at the surface of Mcl1 exhibits a critical role in binding partners selectively via the BH3-domain of pro-apoptotic Bcl2 family members that trigger the downregulation of Mcl1 function. There are several crystal structures of point-mutated pro-apoptotic Bim peptides in complex with Mcl1. However, the mechanistic effects of such point-mutations towards peptide binding and complex stability still remain unexplored. Here, the effects of the reported point mutations in Bim peptides and their binding mechanisms to Mcl1 were computationally evaluated using atomistic-level steered molecular dynamics (SMD) simulations. A range of external-forces and constant-velocities were applied to the Bim peptides to uncover the mechanistic basis of peptide dissociation from the CBG of Mcl1. Although the peptides showed similarities in their dissociation pathways, the peak rupture forces varied significantly. According to simulations results, the disruption of the conserved polar contacts at the complex interface causes a sequential release of the peptides from the CBG of Mcl1. Overall, the results obtained from the current study may provide valuable insights for the development of novel anti-cancer peptide-inhibitors that can downregulate Mcl1's function.
AB - Mcl1 is an important anti-apoptotic member of the Bcl2 family proteins that are upregulated in several cancer malignancies. The canonical binding groove (CBG) located at the surface of Mcl1 exhibits a critical role in binding partners selectively via the BH3-domain of pro-apoptotic Bcl2 family members that trigger the downregulation of Mcl1 function. There are several crystal structures of point-mutated pro-apoptotic Bim peptides in complex with Mcl1. However, the mechanistic effects of such point-mutations towards peptide binding and complex stability still remain unexplored. Here, the effects of the reported point mutations in Bim peptides and their binding mechanisms to Mcl1 were computationally evaluated using atomistic-level steered molecular dynamics (SMD) simulations. A range of external-forces and constant-velocities were applied to the Bim peptides to uncover the mechanistic basis of peptide dissociation from the CBG of Mcl1. Although the peptides showed similarities in their dissociation pathways, the peak rupture forces varied significantly. According to simulations results, the disruption of the conserved polar contacts at the complex interface causes a sequential release of the peptides from the CBG of Mcl1. Overall, the results obtained from the current study may provide valuable insights for the development of novel anti-cancer peptide-inhibitors that can downregulate Mcl1's function.
KW - Mcl1-Bim complex
KW - Cancer inhibitors
KW - Molecular dynamics simulations
KW - Steered molecular dynamics simulations
KW - Potential mean forces estimation
U2 - 10.1016/j.ijbiomac.2020.04.243
DO - 10.1016/j.ijbiomac.2020.04.243
M3 - Article
SN - 0141-8130
VL - 158
SP - 364
EP - 374
JO - International Journal of Biological Macromolecules
JF - International Journal of Biological Macromolecules
ER -