Prediction of peptides binding to the PKA RIIα subunit using a hierarchical strategy

Motivation: Favorable interaction between the regulatory subunit of the cAMP-dependent protein kinase (PKA) and a peptide in A-kinase anchoring proteins (AKAPs) is critical for translocating PKA to the subcellular sites where the enzyme phosphorylates its substrates. It is very hard to identify AKAPs peptides binding to PKA due to the high sequence diversity of AKAPs. Results: We propose a hierarchical and efficient approach, which combines molecular dynamics (MD) simulations, free energy calculations, virtual mutagenesis (VM) and bioinformatics analyses, to predict peptides binding to the PKA RII alpha regulatory subunit in the human proteome systematically. Our approach successfully retrieved 15 out of 18 documented RII alpha-binding peptides. Literature curation supported that many newly predicted peptides might be true AKAPs. Here, we present the first systematic search for AKAP peptides in the human proteome, which is useful to further experimental identification of AKAPs and functional analysis of their biological roles.