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Long-range molecular dynamics show that inactive forms of Protein Kinase A are more dynamic than active forms

Kalaivani, R and Narwani, TJ and de Brevern, AG and Srinivasan, N (2019) Long-range molecular dynamics show that inactive forms of Protein Kinase A are more dynamic than active forms. In: PROTEIN SCIENCE, 28 (3). pp. 543-560.

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Official URL: https://doi.org/10.1002/pro.3556


Many protein kinases are characterized by at least two structural forms corresponding to the highest level of activity (active) and low or no activity, (inactive). Further, protein dynamics is an important consideration in understanding the molecular and mechanistic basis of enzyme function. In this work, we use protein kinase A (PKA) as the model system and perform microsecond range molecular dynamics (MD) simulations on six variants which differ from one another in terms of active and inactive form, with or without bound ligands, C-terminal tail and phosphorylation at the activation loop. We find that the root mean square fluctuations in the MD simulations are generally higher for the inactive forms than the active forms. This difference is statistically significant. The higher dynamics of inactive states has significant contributions from ATP binding loop, catalytic loop, and alpha G helix. Simulations with and without C-terminal tail show this differential dynamics as well, with lower dynamics both in the active and inactive forms if C-terminal tail is present. Similarly, the dynamics associated with the inactive form is higher irrespective of the phosphorylation status of Thr 197. A relatively stable stature of active kinases may be better suited for binding of substrates and detachment of the product. Also, phosphoryl group transfer from ATP to the phosphosite on the substrate requires precise transient coordination of chemical entities from three different molecules, which may be facilitated by the higher stability of the active state.

Item Type: Journal Article
Publisher: WILEY
Additional Information: Copyright of this article belongs to WILEY
Keywords: protein kinase A; molecular dynamics; active and inactive states; functional state; structural flexibility in active and inactive state kinases; protein kinases; STY kinases
Department/Centre: Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited: 01 Mar 2019 05:34
Last Modified: 01 Mar 2019 05:34
URI: http://eprints.iisc.ac.in/id/eprint/61871

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