Application of MM/PBSA colony free energy to loop decoy discrimination: toward correlation between energy and root mean square deviation.

Accurate free energy estimation is needed in many predictive tasks. The molecular mechanics/Poisson-Boltzmann solvent accessible surface area (MM/PBSA) approach has proven to be accurate. However, the correlation between the estimated free energy and the distance (e.g., root mean square deviation [RMSD]) from the most stable conformation is hindered by the strong free energy dependence on minor conformational variations. In this paper, a protocol for MM/PBSA free energy estimation is designed and tested on several loop decoy sets. We show that further integration of MM/PBSA free energy estimator with the colony energy approach makes the correlation between the free energy and RMSD from the native structure apparent, for the test sets on which it could be applied. Our results suggest that (1) the MM/PBSA free energy estimator is able to detect native-like structures for most decoy sets, and (2) application of the colony energy approach greatly hampers the MM/energy strong dependence on minor conformational changes.