Estimating glycosaminoglycan-protein interaction affinity: water dominates the specific antithrombin-heparin interaction. Glycobiology 2016 Oct;26(10):1041-1047
Date
08/09/2016Pubmed ID
27496757Pubmed Central ID
PMC5072149DOI
10.1093/glycob/cww073Scopus ID
2-s2.0-84994831305 (requires institutional sign-in at Scopus site) 15 CitationsAbstract
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.
Author List
Sarkar A, Yu W, Desai UR, MacKerell AD, Mosier PDAuthor
Philip Mosier PhD Assistant Professor in the School of Pharmacy Administration department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AntithrombinsHeparin
Molecular Dynamics Simulation
Proteins
Thermodynamics
Water
