Abstract Number: PB0218
Meeting: ISTH 2020 Congress
Background: Vitamin K epoxide reductase (VKOR), an endoplasmic reticulum membrane protein, is the key enzyme for vitamin K-dependent carboxylation, a posttranslational modification that is essential for the biological functions of coagulation factors. VKOR is the target of the most widely prescribed oral anticoagulant, warfarin. However, the topological structure of VKOR and the mechanism of warfarin’s inhibition of VKOR remain elusive. Additionally, it is not clear why warfarin-resistant VKOR mutations identified in patients significantly decrease warfarin’s binding affinity, but have only a minor effect on vitamin K binding. Here, Using molecular dynamics (MD) simulations, a T-shaped stacking interaction between warfarin and tyrosine residue 139, within the proposed TY139A warfarin-binding motif, was observed. Our findings provide new insights into the dynamics of the binding of warfarin to VKOR, as well as into warfarin’s mechanism of anticoagulation.
Aims: We show that warfarin binds to VKOR based on 3TM model with steered MD simulation.
Methods: MD simulations of warfarin binding to VKOR were performed : step 1, providing an MD-equilibrated 3-TM VKOR in lipid and solvent; step 2, the 40-nanosecond equilibration of warfarin in the ER lumen near a reasonable access point to the interior of VKOR; step 3, steered MD simulation.
Results: As warfarin accesses its binding site, it encounters several hydrophobic residues that are essential for maintaining VKOR’s stable structure. We assume that the interactions between these hydrophobic residues must be weakened to allow warfarin to access its binding pocket during the 448-picosecond steered MD simulation. Our results show a dramatic increase in the minimum distance between L15 and L128, suggesting the opening of the warfarin-binding pocket in VKOR. Thereafter, warfarin appears to penetrate into the new cavity of VKOR
Conclusions: The T-shaped stacking configuration between warfarin and Y139 can happen only in the 3-TM model of VKOR, not the 4-TM model.
To cite this abstract in AMA style:Wu S, Stafford D, Pedersen L, Tie J-. Warfarin and Vitamin K Epoxide Reductase: A Mechanism for Inhibition Using Molecular Dynamics Simulation [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/warfarin-and-vitamin-k-epoxide-reductase-a-mechanism-for-inhibition-using-molecular-dynamics-simulation/. Accessed November 27, 2021.
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