To identify long distance allosteric couplings inside a protein kinase catalytic domain, we took protein kinase A (PKA) as a model system and obtained molecular dynamics trajectories up to 7.8 microseconds in length with various natural ligands bound. We used mutual information and community analysis to identify structurally-contiguous groups of residues exhibiting correlated motions, which we denote as communities. These communities � annotated by function using a wealth of published mutational data � provide a framework for analyzing the local vs. long-range effects of mutations, binding, and phosphorylation. These communities contain community-forming residues with conserved side-chain orientations that provide a semi-rigid center of each community. Futhermore, the communities have conserved cores that persist across different ligand and conformational states. Additionally, we use community maps and Jensen-Shannon Divergence through the freely-available MutInf program to examine how removal of a phosphate from the activation loop alters these communities, how removal of a single Mg2+ion causes global changes in dynamics, and how mutations  might alter activity through subtle conformational changes and changes in dynamics.Figure 1. Community map of PKA. The size of each node represents the number of members of each community, and the edge weights are proportional to the thickness of the lines. The kinase is shown in white and communities are highlighted in red.

Dynamic architecture of protein kinases from microsecond-scale simulations

248th National Meeting (2014)

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