DOI: 10.5061/dryad.qj597
title: Data from: Structure-based network analysis of activation mechanisms in the ErbB family of receptor tyrosine kinases: the regulatory spine residues are global mediators of structural stability and allosteric interactions

description: The ErbB protein tyrosine kinases are among the most important cell
 signaling families and mutation-induced modulation of their activity is
 associated with diverse functions in biological networks and human
 disease. We have combined molecular dynamics simulations of the ErbB
 kinases with the protein structure network modeling to characterize the
 reorganization of the residue interaction networks during conformational
 equilibrium changes in the normal and oncogenic forms. Structural
 stability and network analyses have identified local communities
 integrated around high centrality sites that correspond to the regulatory
 spine residues. This analysis has provided a quantitative insight to the
 mechanism of mutation-induced “superacceptor” activity in oncogenic EGFR
 dimers. We have found that kinase activation may be determined by
 allosteric interactions between modules of structurally stable residues
 that synchronize the dynamics in the nucleotide binding site and the
 αC-helix with the collective motions of the integrating αF-helix and the
 substrate binding site. The results of this study have pointed to a
 central role of the conserved His-Arg-Asp (HRD) motif in the catalytic
 loop and the Asp-Phe-Gly (DFG) motif as key mediators of structural
 stability and allosteric communications in the ErbB kinases. We have
 determined that residues that are indispensable for kinase regulation and
 catalysis often corresponded to the high centrality nodes within the
 protein structure network and could be distinguished by their unique
 network signatures. The optimal communication pathways are also controlled
 by these nodes and may ensure efficient allosteric signaling in the
 functional kinase state. Structure-based network analysis has quantified
 subtle effects of ATP binding on conformational dynamics and stability of
 the EGFR structures. Consistent with the NMR studies, we have found that
 nucleotide-induced modulation of the residue interaction networks is not
 limited to the ATP site, and may enhance allosteric cooperativity with the
 substrate binding region by increasing communication capabilities of
 mediating residues.
description: ForceConstantAnalysis_RawDatawe analyzed structural stability of the regulatory regions in different functional states of the ErbB kinases and characterized mutation-induced changes in stability profiles that may be relevant for activation mechanisms. For this analysis, we employed a number of complementary approaches, including the force constant profiling of residue connectivity, the contact network analysis of residue closeness, the relative solvent accessibility (RSA) evaluation of local residue environment, and the network-based analysis of local contact density. In the ensemble-based force constant analysis, the equilibrium fluctuations of the mean distance between each residue and the rest of the protein were converted into force constants that measure the energy cost of the residue displacement during equilibrium simulations. The high force constants are typically associated with structurally stable residues that display small fluctuations in their distances to other residues and often correspond to highly connect and effectively communicating rigid sites. Previous studies have linked structural stability of functionally important residues with their high connectivity, particularly indicating that catalytic and binding site residues typically have high force constant values, which reflects functional constraints imposed on their movement. Abrupt changes between maxima and minima in the force constant profiles may be associated with the regions bridging structurally rigid and flexible regions, often pointing to the hinge sites. The hypothesis tested in our analysis is that the R-spine residues could effectively mediate structural stability and allosteric interactions via regulatory regions. The analysis revealed that high force constant residues in the catalytic domain are assembled near the αC-helix, αE-helix and αF-helix regions suggesting that structural stability of these structural elements may be critical for allosteric coupling between regulatory regionsProteinStructureNetworkAnalysis_RawData