Conserved Hydrophobic and Hydrophilic Bond Interaction Networks in ErbB Family Kinases

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The EGFR/ErbB/HER family of kinases contains four homologous receptor tyrosine kinases that are important regulatory elements in key signaling pathways. To elucidate the atomistic mechanisms of activation in the ErbB family, we perform molecular dynamics simulations on the three members of the ErbB family with known kinase activity, EGFR, HER2 (ErbB2) and ErbB4, in different molecular contexts: monomer vs. dimer, wildtype vs. mutant. Using bioinformatics and fluctuation analyses of the molecular dynamics trajectories, we relate sequence similarities to similarities in specific bond-interaction networks and similarities in collective dynamical modes. We find that in the active conformation of the ErbB kinases, key loop motions are coordinated through conserved hydrophilic interactions, an activating bond-network consisting of hydrogen bonds and salt bridges. While the inactive conformations show a less extensive inactivating bond network, they sequester key residues and disrupt the activating bond-network. Both conformational states are also stabilized through context-specific hydrophobic interactions. We show that the functional (activating) asymmetric kinase dimer interface forces a corresponding change in the hydrophobic and hydrophilic interactions characterizing the inactivating bond network, resulting in the motion of the αC-helix through allostery. Some of the clinically identified activating kinase mutations of EGFR also act in a similar fashion, disrupting the inactivating bond network. Our molecular dynamics study reveals a fundamental difference in the sequence of events in EGFR activation in comparison to the Src kinase Hck. This work is funded by NSF grants CBET-0730955 and CBET-0853539.