Simulations of heparin : force fields, sequences, and interactions with sclerostin

Janke, Jonathan Joel
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Linhardt, Robert J.
Hahn, Juergen
Gilbert, Ryan
Wang, Chunyu
Garcia, Angel E.
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Biomedical engineering
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As a member of the glycosaminoglycan family of biomolecules, heparin is a highly negatively charged polysaccharide, best known for its anticoagulant activity. The pentasaccharide sequence of heparin responsible for anticoagulant activity is ArixtraTM (also known as fondaparinux), which is an important drug. While the function of ArixtraTM is well characterized, its conformational ensemble is less well known. Thus, the purpose of Chapters 2 and 3 of this thesis is to characterize the conformational ensemble of ArixtraTM using molecular dynamics simulations, with a view towards the best method to simulating heparin (Chapter 2) and the effect of sulfation on the conformational ensemble of ArixtraTM. Chapter 4 is then dedicated to characterizing the heparin binding site of a bone protein known as sclerostin using molecular dynamics simulations. The outcome of this thesis is to provide an in depth understanding of heparin’s conformational ensemble and how it relates to the function of heparin in anticoagulation as well as providing a method to find and characterize heparin binding sites for activities of heparin beyond anticoagulation.
August 2020
School of Engineering
Dept. of Biomedical Engineering
Rensselaer Polytechnic Institute, Troy, NY
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