This paper explores the fallacy of determining conformational energies for polar organic molecules from molecular mechanics force fields. Using Taxol as a test case, it investigates how different force fields can produce downright contradictory results for energetic rankings of Taxol conformations.
The bottom line is simple; do NOT trust energies from force fields. Trust geometries. In case of energies force fields usually overemphasize electrostatic interactions because of lack of explicit solvent representation. Thus sometimes even geometries can be warped because of electrostatics overwhelming the optimization. The one thing force fields are good at calculating on the other hand is sterics.
Running a "complete" conformational search with multiple force fields will usually give you completely different geometries for the global minimum, or at least slightly different ones (depending on the molecule). Thus, trusting the global minimum conformation from any one force field is a big fallacy. Thinking that that global minimum will be the true global minimum in solution is nothing short of blasphemy. And for a bioactive molecule, thinking that the global minimum from a force field search will be the bioactive conformation is just...well, that just means you have been seduced by the dark side of the force field.
Lakdawala, A., Wang, M., Nevins, N., Liotta, D.C., Rusinska-Roszak, D., Lozynski, M., Snyder, J.P. (2001). . BMC Chemical Biology, 1(1), 2. DOI: 10.1186/1472-6769-1-2