Exploring the interactions of EGFR with phosphorylated Mig6 by molecular dynamics simulations and MM-PBSA calculations.

Mig6, a negative regulator, directly binds to epidermal growth factor receptor (EGFR), including Mig6-segment1 and Mig6-segment2. Mig6 requires phosphorylation of Y394 on Mig6-segment2 in order to inhibit EGFR. Two phosphorylation pathways for Y394 have been previously reported and the first way may phosphorylate Y394 primed by Y395 phosphorylation. Besides, the binding mechanism of phosphorylated Mig6-segment2 with EGFR has not been elucidated clearly. Focused on EGFR complex with phosphorylated Mig6-segment2, molecular dynamics (MD) simulations were performed to explore the interactions of Mig6-segment2 with EGFR. Our results indicate a probable phosphorylation pathway on Y394 and some key residues of EGFR play important roles in binding to phosphorylated Mig6-segment2. In addition, a special L-shaped structure was found to be possibly associated with irreversible inhibition of EGFR by Mig6. Our work can give meaningful information to better understand the phosphorylation pathways for Y394 and the interactions of EGFR binding to phosphorylated Mig6-segment2.

[1]  W. L. Jorgensen,et al.  Comparison of simple potential functions for simulating liquid water , 1983 .

[2]  Na Li,et al.  Conversion of MIG6 peptide from the nonbinder to binder of lung cancer-related EGFR by phosphorylation and cyclization , 2017, Artificial cells, nanomedicine, and biotechnology.

[3]  Richard H. Henchman,et al.  Revisiting free energy calculations: a theoretical connection to MM/PBSA and direct calculation of the association free energy. , 2004, Biophysical journal.

[4]  W. Delano.  The PyMOL Molecular Graphics System , 2002 .

[5]  Holger Gohlke,et al.  The Amber biomolecular simulation programs , 2005, J. Comput. Chem..

[6]  P. Kollman,et al.  Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. , 2000, Accounts of chemical research.

[7]  D. Haussler,et al.  The Somatic Genomic Landscape of Glioblastoma , 2013, Cell.

[8]  T. Darden,et al.  Particle mesh Ewald: An N⋅log(N) method for Ewald sums in large systems , 1993 .

[9]  F. Sicheri.  Faculty Opinions recommendation of Inhibition of the EGF receptor by binding of MIG6 to an activating kinase domain interface. , 2007 .

[10]  M. Meyerson,et al.  Structure and mechanism of activity-based inhibition of the EGF-Receptor by Mig6 , 2015, Nature Structural &Molecular Biology.

[11]  D. Leahy,et al.  Tyrosine phosphorylation of mig6 reduces its inhibition of the epidermal growth factor receptor. , 2013, ACS chemical biology.

[12]  K Schulten,et al.  VMD: visual molecular dynamics. , 1996, Journal of molecular graphics.

[13]  Siriluk Rattanabunyong,et al.  Understanding the molecular basis of EGFR kinase domain/MIG-6 peptide recognition complex using computational analyses , 2015, BMC Bioinformatics.

[14]  Akhilesh Pandey,et al.  Comparisons of tyrosine phosphorylated proteins in cells expressing lung cancer-specific alleles of EGFR and KRAS , 2008, Proceedings of the National Academy of Sciences.

[15]  E. Maspero,et al.  A two-tiered mechanism of EGFR inhibition by RALT/MIG6 via kinase suppression and receptor degradation , 2010, The Journal of cell biology.

[16]  Haikuo Zhang,et al.  Overcoming EGFR T790M and C797S resistance with mutant-selective allosteric inhibitors , 2016 .

[17]  Benjamin J. Raphael,et al.  Mutational landscape and significance across 12 major cancer types , 2013, Nature.

[18]  P. Kollman,et al.  Settle: An analytical version of the SHAKE and RATTLE algorithm for rigid water models , 1992 .

[19]  A. Sali,et al.  Modeller: generation and refinement of homology-based protein structure models. , 2003, Methods in enzymology.

[20]  H. Varmus,et al.  Loss of MIG6 Accelerates Initiation and Progression of Mutant Epidermal Growth Factor Receptor-Driven Lung Adenocarcinoma. , 2015, Cancer discovery.

[21]  Chris Sander,et al.  Erratum: The somatic genomic landscape of glioblastoma (Cell (2013) 155 (462-477)) , 2014 .