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Exploring the free-energy landscape of carbohydrate-protein complexes : development and validation of scoring functions considering the binding-site topology

Eid, Sameh and Saleh, Noureldin and Zalewski, Adam and Vedani, Angelo. (2014) Exploring the free-energy landscape of carbohydrate-protein complexes : development and validation of scoring functions considering the binding-site topology. Journal of computer-aided molecular design, Vol. 28, H. 12. pp. 1191-1204.

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Official URL: http://edoc.unibas.ch/dok/A6329099

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Abstract

Carbohydrates play a key role in a variety of physiological and pathological processes and, hence, represent a rich source for the development of novel therapeutic agents. Being able to predict binding mode and binding affinity is an essential, yet lacking, aspect of the structure-based design of carbohydrate-based ligands. We assembled a diverse data set comprising 273 carbohydrate-protein crystal structures with known binding affinity and evaluated the prediction accuracy of a large collection of well-established scoring and free-energy functions, as well as combinations thereof. Unfortunately, the tested functions were not capable of reproducing binding affinities in the studied complexes. To simplify the complex free-energy surface of carbohydrate-protein systems, we classified the studied proteins according to the topology and solvent exposure of the carbohydrate-binding site into five distinct categories. A free-energy model based on the proposed classification scheme reproduced binding affinities in the carbohydrate data set with an r (2) of 0.71 and root-mean-squared-error of 1.25 kcal/mol (N = 236). The improvement in model performance underlines the significance of the differences in the local micro-environments of carbohydrate-binding sites and demonstrates the usefulness of calibrating free-energy functions individually according to binding-site topology and solvent exposure.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Ehemalige Einheiten Pharmazie > Molecular Modeling (Vedani)
UniBasel Contributors:Vedani, Angelo and Eid, Sameh and Zalewski, Adam
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Kluwer
ISSN:0920-654X
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:06 Feb 2015 09:58
Deposited On:06 Feb 2015 09:58

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