Dancing Molecules: Rewiring Cooperative Communications within 14-3-3 ζ Docking Proteins

Allosteric engineering may play a key role in novel drug discovery. As allosteric interactions are often associated with disease states where protein active sites are rendered constitutively active. Due to their role in regulating signal transduction in cells, we attempted to rewire cooperative communications within the 14-3-3 {zeta} docking protein. To avoid disruption of evolutionarily tuned interaction networks, we attempted to do so by applying the \"Fundamental Theory of the Evolution Force: FTEF\". Whereby, we reversed the motion vector of the 14-3-3 {zeta} C terminal tail. We were also able to modify low frequency vibrational modes across 14-3-3 {zeta} conformational ensembles. Notably, synthetic evolution by FTEF anticipated evolution of the 14-3-3 {zeta} docking protein. And accentuated nonrandom patterns of deformation waves resulting in a gain of function mutation characterized by increased protein flexibility. As well as allowed us to discover a genome encoded spatial arrangement of strain that promotes translation of vibrational motions through protein structural layers. We also discovered a 14-3-3 {zeta} evolution blueprint that predetermines evolutional fate of the docking protein. The aforementioned suggests that the evolutionary fate of cells may be encoded in the genome, thusly may be predetermined.\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC=\"FIGDIR/small/683466v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (47K):\norg.highwire.dtl.DTLVardef@1f701a7org.highwire.dtl.DTLVardef@18d7e00org.highwire.dtl.DTLVardef@4b4021org.highwire.dtl.DTLVardef@5f6afe_HPS_FORMAT_FIGEXP M_FIG C_FIG SignificanceAllostery plays a key role in disease. Wherein, mutations redistribute conformational ensembles and render proteins constitutively active. 14-3-3 docking proteins are key signaling proteins involved in multiple signal pathways that effect cell proliferation, cell cycle and apoptosis. Saliently, the 14-3-3 {zeta} isoform is associated with neurodegenerative disease, cancer and glaucoma. Thusly, ability to rewire cooperative communications within 14-3-3 {zeta} offers opportunity for novel drug discovery.