Dynamic architecture of a protein kinase (802.22)

To better understand the mechanism of long distance allosteric signaling inside the protein kinase core using protein kinase A (PKA) as a prototype, we obtained 5μs molecular dynamics trajectories in different liganded and conformational states using the Anton supercomputer, providing for the first time an opportunity to observe intermediate‐timescale conformational transitions in the study of the dynamics of this stable kinase. We used community analysis to identify structurally‐contiguous groups of residues exhibiting correlated motions in the kinase catalytic domain. This dynamic partitioning of the kinase into communities provides a framework for analyzing the local vs. long‐range effects of mutations, binding, phosphorylation, etc. We hypothesize that perturbations will be readily felt within these communities and then propagated possibly to a lesser extent to other elements through correlated motions. Moreover, using a wealth of published mutational data, we can annotate these communities with functions. Our functional annotation of kinase communities provides an extremely valuable framework for viewing a signaling enzyme in terms of functional substructures rather than isolated linear motifs such as secondary structure elements and short three or four residue motifs.Figure 1. Functional annotation of the kinase communitiy map. Each community is shown in red on the structure of PKA. Grant Funding Source : Supported by NIH F32 GM099197, R01 GM19301