Ab initio construction of protein tertiary structures using a hierarchicalapproach

We present a hierarchical method to predict protein tertiary structure mode ls from sequence. We start with complete enumeration of conformations using a simple tetrahedral lattice model. We then build conformations with incre asing detail, and at each step select a subset of conformations using empir ical energy functions with increasing complexity. After enumeration on latt ice, we select a subset of low energy conformations using a statistical res idue-residue contact energy function, and generate all-atom models using pr edicted secondary structure. A combined knowledge-based atomic level energy function is then used to select subsets of the all-atom models. The final predictions are generated using a consensus distance geometry procedure. We test the feasibility of the procedure on a set of 12 small proteins coveri ng a wide range of protein topologies. A rigorous double-blind test of our method was made under the auspices of the CASPS experiment, where we did ab initio structure predictions for 12 proteins using this approach. The perf ormance of our methodology at CASPS is reasonably good and completely consi stent with our initial tests. (C) 2000 Academic Press.