Publication: Understanding the molecular basis of EGFR kinase domain/MIG-6 peptide recognition complex using computational analyses
Issued Date
2015-03-27
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eng
Bibliographic Citation
BMC Bioinformatics. Vol.16, No.103 (2015), 1-16
Suggested Citation
Ninnutt Moonrin, Napat Songtawee, Siriluk Rattanabunyong, Surasuk Chunsrivirot, Wanwimon Mokmak, Sissades Tongsima, Kiattawee Choowongkomon Understanding the molecular basis of EGFR kinase domain/MIG-6 peptide recognition complex using computational analyses. BMC Bioinformatics. Vol.16, No.103 (2015), 1-16. doi:10.1186/s12859-015-0528-x Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/2082
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Title
Understanding the molecular basis of EGFR kinase domain/MIG-6 peptide recognition complex using computational analyses
Abstract
Background
Epidermal growth factor receptor (EGFR) signalling plays a major role in biological processes, including cell proliferation, differentiation and survival. Since the over-expression of EGFR causes human cancers, EGFR is an attractive drug target. A tumor suppressor endogenous protein, MIG-6, is known to suppress EGFR over-expression by binding to the C-lobe of EGFR kinase. Thus, this C-lobe of the EGFR kinase is a potential new target for EGFR kinase activity inhibition. In this study, molecular dynamics (MD) simulations and binding free energy calculations were used to investigate the protein-peptide interactions between EGFR kinase and a 27-residue peptide derived from MIG-6_s1 segment (residues 336–362).
Results
These 27 residues of MIG-6_s1 were modeled from the published MIG-6 X-ray structure. The binding dynamics were detailed by applying the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method to predict the binding free energy. Both van der Waals interactions and non-polar solvation were favorable driving forces for binding process. Six residues of EGFR kinase and eight residues of MIG-6_s1 residues were shown to be responsible for interface binding in which we investigated per residue free energy decomposition and the results from the computational alanine scanning approach. These residues also had higher hydrogen bond occupancies than other residues at the binding interface. The results from the aforementioned calculations reasonably agreed with the previous experimental mutagenesis studies.
Conclusions
Molecular dynamics simulations were used to investigate the interactions of MIG-6_s1 to EGFR kinase domain. Our study provides an insight into such interactions that is useful in guiding the design of novel anticancer therapeutics. The information on our modelled peptide interface with EGFR kinase could be a possible candidate for an EGFR dimerization inhibitor.