Ab initio construction of protein tertiary structures using a hierarchical approach

• Published in: Journal of molecular biology 2000-06, Vol.300 (1), p.171-185
• Main Authors: Xia, Yu, Huang, Enoch S., Levitt, Michael, Samudrala, Ram
• Format: Article
• Language: English
• Subjects: Algorithms; Computer Simulation - trends; Consensus Sequence; decoy approach; discriminatory function; Double-Blind Method; knowledge based; lattice model; Models, Molecular; Molecular Weight; protein structure prediction; Protein Structure, Secondary; Protein Structure, Tertiary; Proteins - chemistry; Proteins - metabolism; Sensitivity and Specificity; Software; Thermodynamics; Time Factors
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1006/jmbi.2000.3835

We present a hierarchical method to predict protein tertiary structure models from sequence. We start with complete enumeration of conformations using a simple tetrahedral lattice model. We then build conformations with increasing detail, and at each step select a subset of conformations using empirical energy functions with increasing complexity. After enumeration on lattice, we select a subset of low energy conformations using a statistical residue-residue contact energy function, and generate all-atom models using predicted 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 covering a wide range of protein topologies. A rigorous double-blind test of our method was made under the auspices of the CASP3 experiment, where we did ab initio structure predictions for 12 proteins using this approach. The performance of our methodology at CASP3 is reasonably good and completely consistent with our initial tests.