Computational Studies on PA-IIL Lectin-Carbohydrate Interactions
N.
K. Mishra,1 P. Kulhánek,1 Z. Kří,1 M. Wimmerová,1, 2 J. Koča1
1National
Centre for Biomolecular Research and 2Department of Organic
Chemistry, Faculty of Science, Masaryk University, Kotlářská 2, Brno 611 37.
Lectins
are proteins of nonimmune origin that non-enzymatically selectively bind to
mono or oligosaccharides. Multifarious activity of carbohydrates in
biophysiological pathway, such as immune activity, tumor metastasis, cell-cell
recognition, bacterial pathogenecity, open an avenue for the
lectin-carbohydrate interaction research, which is also a big challenge for
theoretical modeling due to the polar flexible saccharide moiety. One of the
lectins, PA-IIL that produced by Pseudomonas aeruginosa, which play
significant role in cystic fibrosis disease, motivated our study on
PA-IIL-carbohydrate interactions.
The structure can provide a static view of the
macromolecules, but for the full understanding of protein-ligand interactions
it is necessary to know all the accessible spatial orientations of the ligand
in the receptor binding pocket. It is often seen that the binding energy
calculated over the sampled structure by molecular dynamics could give the
insight of the interactions between protein and ligand.[1, 2] We used the
MM/PBSA approach to calculate the binding free energy of the
lectin-carbohydrate. The entropy contribution to the binding free energies was
obtained by normal mode analysis. Unfortunately these conventional methods are
not precise enough to accurately distinguish the binding order of saccharide
series. Thus, to gain the insight of the spatial orientation of the
monosaccharide and conversely the ligand induced fit in the receptor binding
site, the binding energy and the pocket conform to the specific orientation of
the saccharide was correlated. The spatial proximity of carbohydrate inside the
binding domain is the key factor for the lectin-carbohydrate binding, which was
identified by statistical clustering. One of the interesting finding was ions
behavior, revealing their paramount significance for the binding.
References
1. Bonnet, P.; Bryce, R. A. Protein Sci. 2004, 13, 946-957.
2. P.J. Laitimen, T.; kankare, J. A.; Perakyla, M. Proteins: strucure, Function, and Bioinformatics 2004, 55, 34-43.