A TEST OF LATTICE PROTEIN-FOLDING ALGORITHMS

We report a blind test of lattice-model-based search strategies for fi nding global minima of model protein chains. One of us (E.I.S.) select ed 10 compact conformations of 48-mer chains on the three-dimensional cubic lattice and used their inverse folding algorithm to design HP (H , hydrophobic; P, polar) sequences that should fold to those ''target' ' structures. The sequences, but not the structures, were sent to the UCSF group (K.Y., K.M.F., P.D.T., H.S.C., and K.A.D.), who used two me thods to attempt to find the globally optimal conformations: ''hydroph obic zippers'' and a constraint-based hydrophobic core construction (C HCC) method. The CHCC method found global minima in all cases, and the hydrophobic zippers method found global minima in some cases, in minu tes to hours on workstations. In 9 out of 10 sequences, the CHCC metho d found lower energy conformations than the 48-mers were designed to f old to. Thus the search strategies succeed for the HP model but the de sign strategy does not. For every sequence the global energy minimum w as found to have multiple degeneracy with 10(3) to 10(6) conformations . We discuss the implications of these results for (i) searching confo rmational spaces of simple models of proteins and (ii) how these simpl e models relate to proteins.