A decoy set for the thermostable subdomain from chicken villin headpiece, comparison of different free energy estimators

Background: Estimators of free energies are routinely used to judge the quality of protein structural models. As these estimators still present inaccuracies, they are frequently evaluated by discriminating native or native-like conformations from large ensembles of so-called decoy structures. Results: A decoy set is obtained from snapshots taken from 5 long (100 ns) molecular dynamics (MD) simulations of the thermostable subdomain from chicken villin headpiece. An evaluation of the energy of the decoys is given using: i) a residue based contact potential supplemented by a term for the quality of dihedral angles; ii) a recently introduced combination of four statistical scoring functions for model quality estimation (FRST); iii) molecular mechanics with solvation energy estimated either according to the generalized Born surface area (GBSA) or iv) the Poisson-Boltzmann surface area (PBSA) method. Conclusion: The decoy set presented here has the following features which make it attractive for testing energy scoring functions: 1) it covers a broad range of RMSD values (from less than 2.0 angstrom to more than 12 angstrom); 2) it has been obtained from molecular dynamics trajectories, starting from different non-native-like conformations which have diverse behaviour, with secondary structure elements correctly or incorrectly formed, and in one case folding to a native-like structure. This allows not only for scoring of static structures, but also for studying, using free energy estimators, the kinetics of folding; 3) all structures have been obtained from accurate MD simulations in explicit solvent and after molecular mechanics (MM) energy minimization using an implicit solvent method. The quality of the covalent structure therefore does not suffer from steric or covalent problems. The statistical and physical effective energy functions tested on the set behave differently when native simulation snapshots are included or not in the set and when averaging over the trajectory is performed.