CLUSTERING OF LOW-ENERGY CONFORMATIONS NEAR THE NATIVE STRUCTURES OF SMALL PROTEINS

Recent experimental studies of the denatured state and theoretical ana lyses of the folding landscape suggest that there are a large multipli city of low-energy, partially folded conformations near the native sta te. In this report, we describe a strategy for predicting protein stru cture based on the working hypothesis that there are a greater number of low-energy conformations surrounding the correct fold than there ar e surrounding low-energy incorrect folds, To test this idea, 12 ensemb les of 500 to 1,000 low-energy structures for 10 small proteins were a nalyzed by calculating the rms deviation of the Car coordinates betwee n each conformation and every other conformation in the ensemble. In a ll 12 cases, the conformation with the greatest number of conformation s within 4-Angstrom rms deviation was closer to the native structure t han were the majority of conformations in the ensemble, and in most ca ses it was among the closest I to 5%. These results suggest that, to f old efficiently and retain robustness to changes in amino acid sequenc e, proteins may have evolved a native structure situated within a broa d basin of low-energy conformations, a feature which could facilitate the prediction of protein structure at low resolution.