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Center for Nonlinear Studies |
Glycan array screening is a high throughput method for identifying potential binding partners for carbohydrate receptor proteins. However, such screening provides no insight into the origin of the observed binding or lack of binding among related glycans. When applicable, crystallographic and NMR methods can provide 3D structures for these complexes, however these methods are neither rapid nor high throughput. Computational carbohydrate docking offers one approach to generating putative models for these complexes, the accuracy of which may be greatly enhanced by selecting theoretical models that satisfy all of the observed binding and non-binding interactions identified by experimental screening. Once a minimal binding motif is identified experimentally, this motif is computationally docked to the protein receptor. The optimal theoretical alignment is identified from the numerous docked poses by superimposing (threading) the intact glycan, identified from experimental screening, through each theoretical 3D alignment. By considering both binding and non-binding glycans that contain the minimal motif, it is possible to unambiguously identify the optimal orientation of the ligand in the binding site. This method provides not only a 3D model for the complex, but also a rational explanation for the observed array data. We illustrate this high-throughput approach for the anti-tumor antibody JAA-F11, which recognizes the Thomsen-Friedenreich (TF) alpha-linked antigen. Using recently reported data from screening against the glycan array at the Consortium for Functional Glycomics (CFG) and a crystal structure of the free protein, we derive a 3D structure for the antigen-antibody complex that is fully compatible with the screening results from the CFG glycan array.
Host: Parthasarathi Ramakrishnan, T-6: THEORETICAL BIOLOGY AND BIOPHYSICS, rampartha@lanl.gov, 7-7812