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Issue 8, 2019
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Na+-binding modes involved in thrombin's allosteric response as revealed by molecular dynamics simulations, correlation networks and Markov modeling

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Abstract

The monovalent sodium ion (Na+) is a critical modulator of thrombin. However, the mechanism of thrombin's activation by Na+ has been widely debated for more than twenty years. Details of the linkage between thrombin and Na+ remain vague due to limited temporal and spatial resolution in experiments. In this work, we combine microsecond scale atomic-detailed molecular dynamics simulations with correlation network analyses and hidden Markov modeling to probe the detailed thermodynamic and kinetic picture of Na+-binding events and their resulting allosteric responses in thrombin. We reveal that ASP189 and ALA190 comprise a stable Na+-binding site (referred as “inner” Na+-binding site) along with the previously known one (referred as “outer” Na+-binding site). The corresponding newly identified Na+-binding mode introduces significant allosteric responses in thrombin's regulatory regions by stabilizing selected torsion angles of residues responsive to Na+-binding. Our Markov model indicates that the bound Na+ prefers to transfer between the two Na+-binding sites when an unbinding event takes place. These results suggest a testable hypothesis of a substrate-driven Na+ migration (ΔG ∼ 1.7 kcal mol−1) from the “inner” Na+-binding site to the “outer” one during thrombin's catalytic activities. The binding of a Na+ ion at the “inner” Na+-binding site should be inferred as a prerequisite for thrombin's efficient recognition to the substrate, which opens a new angle for our understanding of Na+-binding's allosteric activation on thrombin and sheds light on detailed processes in thrombin's activation.

Graphical abstract: Na+-binding modes involved in thrombin's allosteric response as revealed by molecular dynamics simulations, correlation networks and Markov modeling

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Publication details

The article was received on 27 Nov 2018, accepted on 28 Jan 2019 and first published on 28 Jan 2019


Article type: Paper
DOI: 10.1039/C8CP07293K
Citation: Phys. Chem. Chem. Phys., 2019,21, 4320-4330

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    Na+-binding modes involved in thrombin's allosteric response as revealed by molecular dynamics simulations, correlation networks and Markov modeling

    J. Xiao and F. R. Salsbury, Phys. Chem. Chem. Phys., 2019, 21, 4320
    DOI: 10.1039/C8CP07293K

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