I performed a single point energy calculation using ONIOM in Gaussian 09. In my ONIOM calculation, I included 18 residues and the ligand in the high layer, while the rest of the enzyme was in the low layer. I performed this calculation for two complexes with different ligands but the same 18 residues in the high layer. I obtained ONIOM energy values, but I'm not sure how to interpret and compare these values to determine whether Ligand A is better than Ligand B. I have been searching for an answer for days but have not been able to find anything.
How did you consider the pose of each ligand at your binding site? Consider that if for each ligand you change its pose at the binding site that you are modeling with high theory, then its ONIOM energy might be different. If you are not sampling all possible conformations of your degrees of freedom, you are only looking at a small energetic contribution to the total binding free energy of your ligands in the enzyme, in particular, it would be a 'potential energy' in a single point. If your interest is precisely to compare that single potential energy, then take a reference (e.g. the ONIOM energy of the APO vs the ligand-bound) and compare the difference to it and the relatively difference between ligands.
I performed a molecular docking simulation, and I chose the best pose based on the binding energy output by Autodock Tools.
In my opinion, it is not possible to get an answer to your question from a single point calculation. In both cases, you took an arbitrary point on the potential energy surface, and it makes no sense to compare these points. To answer your question, you need to optimize the geometry in both cases. And then, if the composition of the ligands is different, optimize the ligands separately at a high level of theory, and finally make a thermochemical calculation of the reaction Comp(L1) + L2 = Comp(L2) + L1. In this case, you will receive an answer to your question. If the composition of the ligands is the same, just compare the total energies.
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