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Toward optimal fragment generations for ab initio protein structure assembly.

ABSTRACT: Fragment assembly using structural motifs excised from other solved proteins has shown to be an efficient method for ab initio protein-structure prediction. However, how to construct accurate fragments, how to derive optimal restraints from fragments, and what the best fragment length is are the basic issues yet to be systematically examined. In this work, we developed a gapless-threading method to generate position-specific structure fragments. Distance profiles and torsion angle pairs are then derived from the fragments by statistical consistency analysis, which achieved comparable accuracy with the machine-learning-based methods although the fragments were taken from unrelated proteins. When measured by both accuracies of the derived distance profiles and torsion angle pairs, we come to a consistent conclusion that the optimal fragment length for structural assembly is around 10, and at least 100 fragments at each location are needed to achieve optimal structure assembly. The distant profiles and torsion angle pairs as derived by the fragments have been successfully used in QUARK for ab initio protein structure assembly and are provided by the QUARK online server at http://zhanglab.ccmb. med.umich.edu/QUARK/.

SUBMITTER: Xu D

PROVIDER: S-EPMC3551984 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Toward optimal fragment generations for ab initio protein structure assembly.

Xu Dong D Zhang Yang Y

Proteins 20121016 2

Fragment assembly using structural motifs excised from other solved proteins has shown to be an efficient method for ab initio protein-structure prediction. However, how to construct accurate fragments, how to derive optimal restraints from fragments, and what the best fragment length is are the basic issues yet to be systematically examined. In this work, we developed a gapless-threading method to generate position-specific structure fragments. Distance profiles and torsion angle pairs are then ...[more]

PMID: 22972754

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Project description:We have developed a new combined approach for ab initio protein structure prediction. The protein conformation is described as a lattice chain connecting C(alpha) atoms, with attached C(beta) atoms and side-chain centers of mass. The model force field includes various short-range and long-range knowledge-based potentials derived from a statistical analysis of the regularities of protein structures. The combination of these energy terms is optimized through the maximization of correlation for 30 x 60,000 decoys between the root mean square deviation (RMSD) to native and energies, as well as the energy gap between native and the decoy ensemble. To accelerate the conformational search, a newly developed parallel hyperbolic sampling algorithm with a composite movement set is used in the Monte Carlo simulation processes. We exploit this strategy to successfully fold 41/100 small proteins (36 approximately 120 residues) with predicted structures having a RMSD from native below 6.5 A in the top five cluster centroids. To fold larger-size proteins as well as to improve the folding yield of small proteins, we incorporate into the basic force field side-chain contact predictions from our threading program PROSPECTOR where homologous proteins were excluded from the data base. With these threading-based restraints, the program can fold 83/125 test proteins (36 approximately 174 residues) with structures having a RMSD to native below 6.5 A in the top five cluster centroids. This shows the significant improvement of folding by using predicted tertiary restraints, especially when the accuracy of side-chain contact prediction is >20%. For native fold selection, we introduce quantities dependent on the cluster density and the combination of energy and free energy, which show a higher discriminative power to select the native structure than the previously used cluster energy or cluster size, and which can be used in native structure identification in blind simulations. These procedures are readily automated and are being implemented on a genomic scale.

Dataset Information

Toward optimal fragment generations for ab initio protein structure assembly.

Publications

Toward optimal fragment generations for ab initio protein structure assembly.

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