Study of the affinity between the protein kinase PKA and peptide substrates derived from kemptide using molecular dynamics simulations and MM/GBSA

• Published in: PloS one 2014-10, Vol.9 (10), p.e109639-e109639
• Main Authors: Mena-Ulecia, Karel, Vergara-Jaque, Ariela, Poblete, Horacio, Tiznado, William, Caballero, Julio
• Format: Article
• Language: English
• Subjects: Affinity; Amino acids; Analysis; Animals; Atomic structure; Biochemistry; Catalysis; Chemical properties; Computation; Computational chemistry; Computer applications; Computer simulation; Cyclic AMP-Dependent Protein Kinases - chemistry; Cyclic AMP-Dependent Protein Kinases - metabolism; Drug resistance; Free energy; Kinases; Kinetics; Ligands; Mathematical analysis; Mice; Molecular dynamics; Molecular Dynamics Simulation; Mutation; Oligopeptides - chemistry; Oligopeptides - metabolism; Peptides; Phosphorylation; Physical Sciences; Physiology; Protein Binding; Protein kinase A; Protein kinases; Proteins; Software packages; Solvents; Substrate Specificity; Substrates; Thermodynamics; Values
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0109639

We have carried out a protocol in computational biochemistry including molecular dynamics (MD) simulations and MM/GBSA free energy calculations on the complex between the protein kinase A (PKA) and the specific peptide substrate Kemptide (LRRASLG). We made the same calculations on other PKA complexes that contain Kemptide derivatives (with mutations of the arginines, and with deletions of N and C-terminal amino acids). We predicted shifts in the free energy changes from the free PKA to PKA-substrate complex (ΔΔG(E→ES)) when Kemptide structure is modified (we consider that the calculated shifts correlate with the experimental shifts of the free energy changes from the free PKA to the transition states (ΔΔG(E→TS)) determined by the catalytic efficiency (k(cat)/K(M)) changes). Our results demonstrate that it is possible to predict the kinetic properties of protein kinases using simple computational biochemistry methods. As an additional benefit, these methods give detailed molecular information that permit the analysis of the atomic forces that contribute to the affinity between protein kinases and their substrates.