ESTONIAN ACADEMY
PUBLISHERS
eesti teaduste
akadeemia kirjastus
PUBLISHED
SINCE 1952
 
Proceeding cover
proceedings
of the estonian academy of sciences
ISSN 1736-7530 (Electronic)
ISSN 1736-6046 (Print)
Impact Factor (2022): 0.9
Research article
Computational modeling of cAMP­-dependent protein kinase allostery; pp. 393–401
PDF | https://doi.org/10.3176/proc.2023.4.04

Authors
Andrei Izvolski, Aleksei Kuznetsov
Abstract

Allosteric regulation by ATP of peptide binding with a cAMP-dependent protein kinase catalytic subunit was com­putationally modeled by combining conventional docking analysis and molecular dynamics calculations. It was found that the peptide docking energy was dependent on peptide structure, and, moreover, this energy was also different for the free enzyme and the enzyme–ATP complex. This difference was used to model the allosteric effect of ATP on peptide binding. The same computational analysis revealed that ligand binding reduced the root-mean-square fluctuation (RMSF) values of the enzyme backbone αC atoms, pointing to a ligand-induced reduction in intrinsic conformational dynamics of the protein. As this stiffening of the conformation was induced by the binding of ATP as well as peptides, and its magnitude was in correlation with the ligand binding energy, it was suggested that the modulation of protein conformational dynamics may be responsible for the allosteric regulation of binding effectiveness through the alteration of ligand off-rate from the binding site. This means that the atomic network of interactions, which determines the molecular recognition of the peptide substrate in its binding site, is not changed by allostery, but the intensity of these interactions is affected. This change modulates the overall ligand binding effectiveness and is recognized as an allosteric effect.

References

Changeux, J.-P. 2011. 50th anniversary of the word “allosteric”. Protein Sci.20(7), 1119–1124. 
https://doi.org/10.1002/pro.658

Chen, Y.-C. 2015. Beware of docking! Trends Pharmacol. Sci.36(2), 78–95. 
https://doi.org/10.1016/j.tips.2014.12.001

Cornish-Bowden, A. 2014. Understanding allosteric and coop-erative interactions in enzymes. FEBS J.281(2), 621–632. 
https://doi.org/10.1111/febs.12469

Cui, Q., Karplus, M. 2008. Allostery and cooperativity revisited. Protein Sci.17(8), 1295–1307. 
https://doi.org/10.1110/ps.03259908

Hess, B., Kutzner, C., van der Spoel, D. and Lindahl, E. 2008. GROMACS 4: algorithms for highly efficient, load-bal­anced, and scalable molecular simulation. J. Chem. Theory Comput.4(3), 435–447. 
https://doi.org/10.1021/ct700301q

Izvolski, A., Järv, J. and Kuznetsov, A. 2013. Computer model­ing of the dynamic properties of the cAMP-dependent protein kinase catalytic subunit. Comput. Biol. Chem., 47, 66–70. 
https://doi.org/10.1016/j.compbiolchem.2013.06.004

Järv, J. and Ragnarsson, U. 1991. Linear free energy relationships in cAMP-dependent protein kinase reactions with synthetic substrates. Bioorg. Chem.19(1), 77–87. 
https://doi.org/10.1016/0045-2068(91)90045-Q

Kivi, R., Jemth, P. and Järv, J. 2014. Thermodynamic aspects of cAMP dependent protein kinase catalytic subunit allostery.  Protein J.33(4), 386393. 
https://doi.org/10.1007/s10930-014-9570-1

Koshland, D. E., Jr., Némethy, G. and Filmer, D. 1966. Com­parison of experimental binding data and theoretical models in proteins containing subunits. Biochemistry5(1), 365–385. 
https://doi.org/10.1021/bi00865a047

Kuznetsov, A. and Järv, J. 2008. Single-subunit allostery in the kinetics of peptide phosphorylation by protein kinase A. Proc. Estonian Acad. Sci.57(4), 247–254.
https://doi.org/10.3176/proc.2008.4.07

Kuznetsov, A. and Järv, J. 2009. Ligand structure controlled allostery in cAMP-dependent protein kinase catalytic sub­unit. Cent. Eur. J. Biol.4, 131–141. 
https://doi.org/10.2478/s11535-009-0012-6

Laskowski, R. A., Gerick, F. and Thornton, J. M. 2009. The structural basis of allosteric regulation in proteins. FEBS Lett.583(11), 1692–1698. 
https://doi.org/10.1016/j.febslet.2009.03.019

Li, C., Ma, N., Wang, Y., Wang, Y. and Chen G. 2014. Molecular dynamics simulation studies on the positive cooperativity of the Kemptide substrate with protein kinase A induced by the ATP ligand. J. Phys. Chem. B.118(5), 1273–1287. 
https://doi.org/10.1021/jp411111g

Masterson, L. R., Mascioni, A., Traaseth, N. J., Taylor, S. S. and Veglia, G. 2008. Allosteric cooperativity in protein kinase A. Proc. Natl. Acad. Sci. U.S.A.105(2), 506–511. 
https://doi.org/10.1073/pnas.0709214104

Masterson, L. R., Cembran, A., Shi, L. and Veglia, G. 2012. Allostery and binding cooperativity of the catalytic subunit of protein kinase A by NMR spectroscopy and molecular dynamics simulations. Adv. Protein Chem. Struct. Biol.87, 363–389. 
https://doi.org/10.1016/b978-0-12-398312-1.00012-3

Mena-Ulecia, K., Vergara-Jaque, A., Poblete, H., Tiznado, W. and Caballero, J. 2014. Study of the affinity between the protein kinase PKA and peptide substrates derived from kemptide using molecular dynamics simulations and MM/GBSA. PloS ONE9(10), e109639. 
https://doi.org/10.1371/journal.pone.0109639

Monod, J., Wyman, J., Changeaux, J.-P. 1965. On the nature of allosteric transitions: a plausible model. J. Mol. Biol.12, 88–118. 
https://doi.org/10.1016/S0022-2836(65)80285-6

Segel, I. H. 1975. Enzyme Kinetics. John Wiley & Sons, New York, London, Sydney, Toronto, 274–293. 

Seo, M.-H., Park, J., Kim, E., Hohng, S. and Kim, H.-S. 2014. Protein conformational dynamics dictate the binding affinity for a ligand. Nat. Commun.5, 3724. 
https://doi.org/10.1038/ncomms4724

Trott, O. and Olson, A. J. 2010. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J. Comput. Chem.31(2), 455–461. 
https://doi.org/10.1002/jcc.21334

Wang, Z. and Cole, P. A. 2014. Catalytic mechanisms and regulation of protein kinases. Methods Enzymol.548, 1–21. 
https://doi.org/10.1016/b978-0-12-397918-6.00001-x

Zetterqvist, Ö. and Ragnarsson, U. 1982. The structural requirements of substrates of cyclic AMP-dependent protein kinase. FEBS Lett.139(2), 287–290. 
https://doi.org/10.1016/0014-5793(82)80872-7

Zetterqvist, Ö., Ragnarsson, U., Humble, E., Berglund, L. and Engström, L. 1976. The minimum substrate of cyclic AMP-stimulated protein kinase, as studied by synthetic peptides representing the phosphorylatable site of pyruvate kinase (type L) of rat liver. Biochem. Biophys. Res. Commun.70(3), 696–703. 
https://doi.org/10.1016/0006-291X(76)90648-3

Zheng, J., Trafny, E. A., Knighton, D. R., Xuong, N. H., Taylor, S. S., Ten Eyck, L. F. et al. 1993. 2.2 Å refined crystal structure of the catalytic subunit of cAMP-dependent protein kinase complexed with MnATP and a peptide inhibitor. Acta Crystallogr. D49(Pt. 3), 362–365. 
https://doi.org/10.1107/s0907444993000423

Back to Issue