title: Exploring the free-energy landscape of carbohydrate-protein complexes: development and validation of scoring functions considering the binding-site topology.
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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland, eid@bio.mx.
authors.forename: Sameh
authors.initials: S
authors.lastname: Eid
authors.forename: Noureldin
authors.initials: N
authors.lastname: Saleh
authors.forename: Adam
authors.initials: A
authors.lastname: Zalewski
authors.forename: Angelo
authors.initials: A
authors.lastname: Vedani
mesh_terms: D001665:Binding Sites; D002241:Carbohydrates / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry*; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D002241:Carbohydrates; D008024:Ligands; D046912:Multiprotein Complexes; D011506:Proteins