title: Estimating glycosaminoglycan-protein interaction affinity: water dominates the specific antithrombin-heparin interaction.
abstract: Glycosaminoglycan (GAG)-protein interactions modulate many important biological processes. Structure-function studies on GAGs may reveal probes and drugs, but their structural complexity and highly acidic nature confound such work. Productivity will increase if we are able to identify tight-binding oligosaccharides in silico. An extension of the CHARMM force field is presented to enable modeling of polysaccharides containing sulfamate functionality, and is used to develop a reliable alchemical free-energy perturbation protocol that estimates changes in affinity for the prototypical heparin-antithrombin system to within 2.3 kcal/mol using modest simulation times. Inclusion of water is crucial during simulation as solvation energy was equal in magnitude to the sum of all other thermodynamic factors. In summary, we have identified and optimized a reliable method for estimation of GAG-protein binding affinity, and shown that solvation is a crucial component in GAG-protein interactions.
authors: Department of Basic Pharmaceutical Sciences, Fred Wilson School of Pharmacy, High Point University, One University Parkway, High Point, NC 27268, USA asarkar1@highpoint.edu pdmosier@vcu.edu.|Department of Medicinal Chemistry and Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, PO Box 980133, Richmond, VA 23298, USA.
authors: Aurijit
authors: A
authors: Sarkar
authors: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, USA.
authors: Wenbo
authors: W
authors: Yu
authors: Department of Medicinal Chemistry and Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, PO Box 980133, Richmond, VA 23298, USA.
authors: Umesh R
authors: UR
authors: Desai
authors: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, USA.
authors: Alexander D
authors: AD
authors: MacKerell
authors: Department of Medicinal Chemistry and Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, PO Box 980133, Richmond, VA 23298, USA asarkar1@highpoint.edu pdmosier@vcu.edu.
authors: Philip D
authors: PD
authors: Mosier
mesh_terms: D000991:Antithrombins / Q000737:chemistry*; D006493:Heparin / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D011506:Proteins / Q000737:chemistry*; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*
chemical_list: D000991:Antithrombins; D011506:Proteins; D014867:Water; D006493:Heparin
keywords: CHARMM; desolvation; free-energy perturbation; molecular dynamics; specificity