# Molecular Basis of Membrane Binding and Activation of Coagulation Factors

> **NIH NIH F31** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2020 · $50,520

## Abstract

Project Summary
A molecular understanding of the coagulation cascade is key to more effectively addressing the public health burden
represented by thrombotic disorders and hemophilia. Thrombosis is a leading cause of morbidity and mortality, respon-
sible for approximately 10 million deaths per year worldwide and ⇠2 million venous thromboembolism events per year in
the United States alone. The cellular membrane is central to the clotting cascade, as it provides a platform for nearly all
coagulation reactions. Specific anionic phospholipids play a complex role in regulating the cascade through atomic-level
interactions with coagulation factor membrane anchors. Closely related membrane anchors show markedly differen-
tial binding and specificity to anionic lipids, phenomena yet to be adequately explained owing to a lack of detailed
structural information. There is also a dearth of atomic-level structural information regarding the membrane-bound
macromolecular complexes vital to spurring clot formation as a result of the membrane dependence of coagulation
complex formation. The objectives of this application are to elucidate the pivotal role of anionic phospholipid specificity
and membrane binding affinity in regulation of coagulation (Aim 1), and to develop the first complete structural model
of a ternary coagulation complex integrating all available experimental information and taking the role of the membrane
into account (Aim 2). In Aim 1, membrane-bound models of GLA domains, membrane anchors common to vitamin
K-dependent coagulation factors, will be developed in lipid compositions of interest using an accelerated membrane
representation to capture spontaneous membrane binding and to achieve enhance sampling of protein-lipid interac-
tions. Advanced free energy calculations will then be performed to determine GLA domain membrane binding affinity.
In Aim 2, protein-protein docked structures of the extrinsic ternary complex will first be developed incorporating all avail-
able experimental information. These initial approximate structures will then be used to determine collective variables,
or measures of degree of complex formation, along which to apply force in nonequilibrium (biased) molecular dynamics
simulations of ternary complex formation. The nonequilibrium simulations will be performed on a phospholipid bilayer
to fully take into account the effects of membrane interactions. The results of the computational studies in Aims 1
and 2 will be used to identify key protein-protein and protein-lipid interactions and these interactions will be further
examined using experimental mutagenesis studies. The knowledge gained through this work has potential to allow
development of novel therapies with targeted specificity, such as thrombotic inhibitors targeting specific GLA domains
and recombinant mutant coagulation factors of increased potency for treating hemophilia.

## Key facts

- **NIH application ID:** 9994350
- **Project number:** 5F31HL136155-04
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Melanie Muller
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2017-08-16 → 2021-08-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994350

## Citation

> US National Institutes of Health, RePORTER application 9994350, Molecular Basis of Membrane Binding and Activation of Coagulation Factors (5F31HL136155-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9994350. Licensed CC0.

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