NATIVE-LIKE TOPOLOGY ASSEMBLY OF SMALL PROTEINS USING PREDICTED RESTRAINTS IN MONTE-CARLO FOLDING SIMULATIONS

By incorporating predicted secondary and tertiary restraints derived f rom multiple sequence alignments into ab initio folding simulations, i t has been possible to assemble native-like tertiary structures for a test set of 19 nonhomologous proteins ranging from 29 to 100 residues in length and representing all secondary structural classes. Secondary structural restraints are provided by the PHD secondary structure pre diction algorithm that incorporates multiple sequence information. Mul tiple sequence alignments also provide predicted tertiary restraints v ia a two-step process: First, seed side chain contacts are selected fr om a correlated mutation analysis, and then an inverse folding algorit hm expands these seed contacts, The predicted secondary and tertiary r estraints are incorporated into a lattice-based, reduced protein model for structure assembly and refinement. The resulting native-like topo logies exhibit a coordinate root-mean-square deviation from native for the whole chain between 3.1 and 6.7 Angstrom, with values ranging fro m 2.6 to 4.1 Angstrom over approximate to 80% of the structure, Overal l, this study suggests that the use of restraints derived from multipl e sequence alignments combined with a fold assembly algorithm is a pro mising approach to the prediction of the global topology of small prot eins.