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The Force-Driven Conformations of Heparin Studied with Single Molecule Force Microscopy

Piotr E. Marszalek ^*, Andres F. Oberhauser , Hongbin Li  and Julio M. Fernandez 

^* Department of Mechanical Engineering and Material Sciences, Duke University, Durham, North Carolina 27708 USA; Department of Physiology and Biophysics, University of Texas Medical Branch, Galveston, Texas 77555 USA; and Department of Biological Sciences, Columbia University, New York, New York 10027 USA

Correspondence: Address reprint requests to Julio M. Fernandez, Dept. of Biological Sciences, Columbia University, New York, NY 10027 USA. E-mail: jfernandez{at}columbia.edu.

Using single molecule force spectroscopy we examine the response of heparin chains to mechanical stretching. We find that at forces below 200 pN heparin behaves as a simple entropic spring. At 200 pN heparin displays a large enthalpic elasticity, which is evident as a pronounced plateau in the force-extension relationship. We determine that this enthalpic elasticity is produced by sugar rings of heparin flipping to more energetic and more extended conformations. We estimate that in vivo, the forces which stretch heparin are comparable to the forces that trigger conformational transitions in our single molecule atomic force microscopy measurements. We hypothesize that these conformational transitions have biological significance in that they provide a mechanism to finely regulate the affinity of various ligands toward heparin, for example, in secretory granules undergoing exocytosis and during the mechanical interactions between cells and the extracellular matrix.

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