Simulating atomic-level interactions in the coagulation cascade

The reactions that take place within the coagulation cascade are essential for formation of clots. They are critical for wound healing when activated properly, and when improperly activated can result in devastating health consequences. The biochemical reactions that make up the cascade have been extensively mapped experimentally, but the detailed mechanisms of coagulation modulation and protease activation have remained elusive. This is partly due to the atomic-level nature of the highly specific interaction between coagulation proteins and membrane phospholipids which allow spontaneous binding from plasma for a number of coagulation proteins at the initiation of clotting. Several important coagulation proteins are also highly flexible, which has made experimental characterization of their complete structures at atomic resolution prohibitively difficult. Computational methodologies provide a unique means of investigating atomic-level interactions of the blood coagulation cascade that are out of reach with experimental methods. Here, we present our findings probing protein-lipid interactions and complex formation of blood coagulation proteins using computational means. Molecular dynamics simulations have been used to model spontaneous membrane binding and protein-lipid interactions of the membrane binding domains of factor X, factor VII, and factor IX at an atomic level. Building on these simulations, we developed an atomic-level, membrane-bound model of the ternary extrinsic complex of blood coagulation using a novel computational methodology combining nonequilibrium molecular dynamics, specialized membrane bilayer representations, and protein-protein docking. Finally, we will present our atomic-level model of tissue factor:factor VIIa bound to XK1, a tissue factor protease inhibitor and factor X hybrid molecule, and discuss potential for future approaches combining experimental and computational methodologies to probe interactions in the coagulation cascade.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biophysics & Computnl Biology

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2022

Author dc:creator

• Muller, Melanie P.

Contributors dc:contributor

• Tajkhorshid, Emad
• Shukla, Diwkar
• Morrissey, James H
• Rienstra, Chad

• extrinsic complex
• factor X
• factor VII
• protein-lipid interactions

Statement dc:rights

• Copyright 2022 Melanie P. Muller

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/116027

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F116027