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.
authors.affiliation: Department of Biochemistry, Faculty of Science, Kasetsart University, 50 Ngam, Wong Wan Rd, Bangkok, Chatuchak, 10900, Thailand. moonrin_jear@hotmail.com.
authors.forename: Ninnutt
authors.initials: N
authors.lastname: Moonrin
authors.affiliation: Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok, 10700, Thailand. napat.son@mahidol.ac.th.
authors.forename: Napat
authors.initials: N
authors.lastname: Songtawee
authors.affiliation: Department of Biochemistry, Faculty of Science, Kasetsart University, 50 Ngam, Wong Wan Rd, Bangkok, Chatuchak, 10900, Thailand. fscislra@ku.ac.th.
authors.forename: Siriluk
authors.initials: S
authors.lastname: Rattanabunyong
authors.affiliation: Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, Pathum Wan, 10330, Thailand. surasak.ch@chula.ac.th.
authors.forename: Surasuk
authors.initials: S
authors.lastname: Chunsrivirot
authors.affiliation: Genetic Engineering Interdisciplinary Program, Graduate School, Kasetsart University, 50 Ngam Wong Wan Rd, Bangkok, Chatuchak, 10900, Thailand. wanwimon.mok@biotec.or.th.|Genome Technology Research Unit, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency (NSTDA), 113 Thailand Science Park, Phahonyothin Road, Khlong Nueng, Pathum Thani, Khlong Luang, 12120, Thailand. wanwimon.mok@biotec.or.th.
authors.forename: Wanwimon
authors.initials: W
authors.lastname: Mokmak
authors.affiliation: Genome Technology Research Unit, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency (NSTDA), 113 Thailand Science Park, Phahonyothin Road, Khlong Nueng, Pathum Thani, Khlong Luang, 12120, Thailand. sissades@biotec.or.th.
authors.forename: Sissades
authors.initials: S
authors.lastname: Tongsima
authors.affiliation: Department of Biochemistry, Faculty of Science, Kasetsart University, 50 Ngam, Wong Wan Rd, Bangkok, Chatuchak, 10900, Thailand. fsciktc@ku.ac.th.|Genome Technology Research Unit, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency (NSTDA), 113 Thailand Science Park, Phahonyothin Road, Khlong Nueng, Pathum Thani, Khlong Luang, 12120, Thailand. fsciktc@ku.ac.th.|Center for Advanced Studies in Tropical Natural Resources, National Research, University-Kasetsart University, Kasetsart University, Bangkok, Chatuchak, 10900, Thailand. fsciktc@ku.ac.th.
authors.forename: Kiattawee
authors.initials: K
authors.lastname: Choowongkomon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000378:metabolism; D019295:Computational Biology / Q000379:methods; D066246:ErbB Receptors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D016296:Mutagenesis; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C484017:ERRFI1 protein, human; D010455:Peptides; D025521:Tumor Suppressor Proteins; D066246:ErbB Receptors