Protein Flexibility and False Positives detection.

Standard hit identification procedure with QUANTUM software implies screening of a large compound library against a given protein target. An example of such procedure for a small set of compounds with known activities is discussed in another blog entry.

Let us show first that a calculation with flexible protein gives a reasonable prediction of the binding free energy. To do that we selected a set of ~200 protein - ligand complexes from the BindingDB database. The protein-ligand pairs were selected mainly so that the complex is small and therefore the whole calculation is fast. The results are represented on the Figure. The horizontal and the vertical axis represent the calculated and the experimental value of the binding free energy calculated from the complexed positions of the ligand within the protein.

The correlation is clearly there and in a few days I will show that the calculated values demonstrate not only the accuracy, but also a good selectivity.

The other Figure represents the correlation between the results of rigid receptor fast docking procedure (horizontal axis) and the fully flexible binding free energies (vertical axis). Although the rigid protein force field has a decent correlation, it fails to recognize electrostatic clashes and thus leads to a fairly large amount of false positives among the predicted ligands. Only about 10% of all the ligands, all originally predicted in the muM range survives as binders. The trend is also clear: all the binding energy values increase (fully flexible force field gives less binders than the rigid calculation would suggest).