Key result
Molecular dynamics simulations demonstrate that sodium binding stabilizes the active form of thrombin, shifting the equilibrium probability of the active state from 0.38 to 0.69.
Why the study?
The equilibrium between active E and inactive E forms of thrombin is assumed to be governed by allosteric binding of a Na+ ion, but the transitions require direct simulation.
Does the presence of Na+ induce conformational changes that stabilize the active form of thrombin?
Does the presence of Na+ induce conformational changes that stabilize the active form of thrombin?
Molecular dynamics simulations reveal that sodium binding stabilizes the active conformation of thrombin through specific structural shifts in the Na+ loop and substrate binding site.
Answers are grounded in this paper and cite their sources.
Simulations capture Na+-driven thrombin shifts for the first time; extends molecular models but leaves clinical anticoagulation effects open.
The equilibrium between active E and inactive E* forms of thrombin is assumed to be governed by the allosteric binding of a Na+ ion. Here we use molecular dynamics simulations and Markov state models to sample transitions between active and inactive states. With these calculations we are able to compare thermodynamic and kinetic properties depending on the presence of Na+. For the first time, we directly observe sodium-induced conformational changes in long-timescale computer simulations. Thereby, we are able to explain the resulting change in activity. We observe a stabilization of the active form in presence of Na+ and a shift towards the inactive form in Na+-free simulations. We identify key structural features to quantify and monitor this conformational shift. These include the accessibility of the S1 pocket and the reorientation of W215, of R221a and of the Na+ loop. The structural characteristics exhibit dynamics at various timescales: Conformational changes in the Na+ binding loop constitute the slowest observed movement. Depending on its orientation, it induces conformational shifts in the nearby substrate binding site. Only after this shift, residue W215 is able to move freely, allowing thrombin to adopt a binding-competent conformation.
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Kahler et al. (2020) studied this question. Sodium (Na+) binding vs. Na+-free environment was evaluated on Probability of the active (E-like) conformational state. Molecular dynamics simulations demonstrate that sodium binding stabilizes the active form of thrombin, shifting the equilibrium probability of the active state from 0.38 to 0.69.
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