University of Illinois Urbana-Champaign

Simulating atomic-level interactions in the coagulation cascade

Muller, Melanie P.

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

Description

Title
Simulating atomic-level interactions in the coagulation cascade
Author(s)
Muller, Melanie P.
Issue Date
2022-07-05
Director of Research (if dissertation) or Advisor (if thesis)
Tajkhorshid, Emad
Doctoral Committee Chair(s)
Tajkhorshid, Emad
Committee Member(s)
  • Shukla, Diwkar
  • Morrissey, James H
  • Rienstra, Chad
Department of Study
School of Molecular & Cell Bio
Discipline
Biophysics & Computnl Biology
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
  • extrinsic complex
  • factor X
  • factor VII, protein-lipid interactions
Abstract
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.
Graduation Semester
2022-08
Type of Resource
Thesis
Handle URL
https://hdl.handle.net/2142/116027
Copyright and License Information
Copyright 2022 Melanie P. Muller

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