TOUCHSTONE: An ab initio protein structure prediction method that uses threading-based tertiary restraints

The successful prediction of protein structure from amino acid sequence req uires two features: an efficient conformational search algorithm and an ene rgy function with a global minimum in the native state. As a step toward ad dressing both issues, a threading-based method of secondary and tertiary re straint prediction has been developed and applied to ab initio folding. Suc h restraints are derived by extracting consensus contacts and. local second ary structure from at least weakly scoring structures that, in some cases, can lack any global similarity to the sequence of interest. Furthermore, to generate representative protein structures, a reduced lattice-based protei n model is used with replica exchange Monte Carlo to explore conformational space. We report results on the application of this methodology, termed TO UCHSTONE, to 65 proteins whose lengths range from 39 to 146 residues. For 4 7 (40) proteins, a cluster centroid whose rms deviation from native is belo w 6.5 (5) Angstrom is found in one of the five lowest energy centroids. The number of correctly predicted proteins increases to 50 when atomic detail is added and a knowledge-based atomic potential is combined with clustered and nonclustered structures for candidate selection. The combination of the ratio of the relative number of contacts to the protein length and the num ber of clusters generated by the folding algorithm is a reliable indicator of the likelihood of successful fold prediction, thereby opening the way fo r genome-scale ab initio folding.