Exploring Dynamic Allostery in Thrombin

ORAL

Abstract

Thrombin is a key enzyme in blood coagulation, essential for maintaining vascular integrity and preventing excessive bleeding. Its dysregulation, however, is linked to pathological conditions such as thrombosis and cancer. Thrombin also serves as a prototypical example of dynamic allostery, undergoing conformational changes in response to diverse binding events. Utilizing molecular dynamics simulations, coupled with statistical analyses and machine learning techniques, we investigate thrombin's allosteric transitions. Specifically, we explore thrombin's switch between slow and fast conformations, its active and inactive states, the influence of Na+ binding, the impact of light chain mutations, and its interactions with various biomolecules. Additionally, we present preliminary findings on allosteric drug design targeting thrombin. Understanding these dynamic behaviors could inform the development of more effective therapeutics aimed at modulating thrombin's function.

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Publication: There likely will be work taken from a variety of publications including a planned one on allosteric drug design with thrombin. As well as the following background work.
Wu, D., and Salsbury, F.R., Jr (2022). Simulations suggest double sodium binding induces unexpected conformational changes in thrombin. J. Mol. Model. 28, 120.

Wu, D., and Salsbury, F.R., Jr (2024). Allosteric modulation of thrombin by thrombomodulin: Insights from logistic regression and statistical analysis of molecular dynamics simulations. ACS Omega 9, 23086–23100.

Wu, D., and Salsbury, F.R., Jr (2023). Unraveling the impact of W215A/E217A mutations on thrombin's dynamics and thrombomodulin binding through molecular dynamics simulations. bioRxiv, 2023.12.20.572552. https://doi.org/10.1101/2023.12.20.572552.

Xiao, J., and Salsbury, F.R. (2017). Molecular dynamics simulations of aptamer-binding reveal generalized allostery in thrombin. J. Biomol. Struct. Dyn. 35, 3354–3369.
Wu, D., Xiao, J., and Salsbury, F.R., Jr (2021). Light Chain Mutation Effects on the Dynamics of Thrombin. J. Chem. Inf. Model. 61, 950–965.

Xiao, J., Melvin, R.L., and Salsbury, F.R., Jr (2019). Probing light chain mutation effects on thrombin via molecular dynamics simulations and machine learning. J. Biomol. Struct. Dyn. 37, 982–999.

Xiao, J., Melvin, R.L., and Salsbury, F.R. (2017). Mechanistic insights into thrombin's switch between "slow" and "fast" forms. Phys. Chem. Chem. Phys. 19, 24522–24533.

Xiao, J., and Salsbury, F.R. (2019). Na+-binding modes involved in thrombin's allosteric response as revealed by molecular dynamics simulations, correlation networks and Markov modeling. Phys. Chem. Chem. Phys. 21, 4320–4330.

Presenters

  • Freddie R Salsbury

    Wake Forest University

Authors

  • Freddie R Salsbury

    Wake Forest University

  • Dizhou Wu

    Wake Forest University

  • Jiajie Xaio

    Wake Forest University