Protein Kinase G (PKG) is a secondary messenger involved in vasodilation signaling.  The PKG regulatory domain consists of two cyclic nucleotide binding domains (CNBD-A and CNBD-B).  The simultaneous binding of cGMP to both CNBDs allosterically activates the catalytic domain.  Recent publication of PKG regulatory domain crystal structures presents new opportunities for the study of protein-ligand association and drug design.  For this purpose we employed thermodynamic integration (TI), a rigorous computational method for determining binding free energies from molecular dynamics (MD) simulations.  In particular the ability of the CNBDs to discriminate between cAMP and cGMP was examined.  As was the protonation state of the cyclic nucleotide phosphorus and the role of the switch helix, the helix which connects the regulatory and catalytic domains.  In addition, virtual screening techniques were used to identify potential lead compounds targeting the PKG regulatory domain.

Examining PKG regulatory domain specificity through thermodynamic integration

243rd National Meeting (2012)

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