title: Effects of oncogenic mutations on the conformational free-energy landscape of EGFR kinase.
abstract: Activating mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase are frequently found in many cancers. It has been suggested that changes in the equilibrium between its active and inactive conformations are linked to its oncogenic potential. Here, we quantify the effects of some of the most common single (L858R and T790M) and double (T790M-L858R) oncogenic mutations on the conformational free-energy landscape of the EGFR kinase domain by using massive molecular dynamics simulations together with parallel tempering, metadynamics, and one of the best force-fields available. Whereas the wild-type EGFR catalytic domain monomer is mostly found in an inactive conformation, our results show a clear shift toward the active conformation for all of the mutants. The L858R mutation stabilizes the active conformation at the expense of the inactive conformation and rigidifies the αC-helix. The T790M gatekeeper mutant favors activation by stabilizing a hydrophobic cluster. Finally, T790M with L858R shows a significant positive epistasis effect. This combination not only stabilizes the active conformation, but in nontrivial ways changes the free-energy landscape lowering the transition barriers.
authors.affiliation: Institute of Structural and Molecular Biology, University College London, London WC1H 0AJ, United Kingdom.
authors.forename: Ludovico
authors.initials: L
authors.lastname: Sutto
authors.forename: Francesco Luigi
authors.initials: FL
authors.lastname: Gervasio
mesh_terms: D019943:Amino Acid Substitution; D020134:Catalytic Domain; D003198:Computer Simulation; D066246:ErbB Receptors / Q000737:chemistry* / Q000235:genetics*; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics; D009857:Oncogenes; D011487:Protein Conformation; D013816:Thermodynamics
chemical_list: C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: conformational changes; resistance-causing mutations