Abstract
The nonlocal nature of the protein-ligand binding problem is investigated via the Gaussian Network Model with which the residues lying along interaction pathways in a protein and the residues at the binding site are predicted. The predictions of the binding site residues are verified by using several benchmark systems where the topology of the unbound protein and the bound protein-ligand complex are known. Predictions are made on the unbound protein. Agreement of results with the bound complexes indicates that the information for binding resides in the unbound protein. Cliques that consist of three or more residues that are far apart along the primary structure but are in contact in the folded structure are shown to be important determinants of the binding problem. Comparison with known structures shows that the predictive capability of the method is significant.
Highlights
Ligand binding is generally known as a local process where the binding molecule finds a suitable location on the protein that has the right shape and the favorable energetic interaction [1].observation of both short and long range conformational changes upon binding led to the suggestion that the full topology of the protein should be taking part in the ligand binding process [2]
The first system that we analyze is an oxireductase, Heme oxygenase (HO) which is responsible for the degradation of heme to biliverdin
Based on the GNM, structural and thermodynamic features of the bound state are predicted by using the unbound structures
Summary
Ligand binding is generally known as a local process where the binding molecule finds a suitable location on the protein that has the right shape and the favorable energetic interaction [1] Observation of both short and long range conformational changes upon binding led to the suggestion that the full topology of the protein should be taking part in the ligand binding process [2]. According to this hypothesis, binding should depend not on the local structure, but rather on an interaction pathway on the protein that takes part in the collective reorganization of the residues to accommodate for the best and most favorable conformation of the protein-ligand complex. The method, which we term as the ‘maximum eigenvalue method’ [9] is based on determining the residues that exchange energy with their
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