Dataset Information

Predicting structures and stabilities for H-type pseudoknots with interhelix loops.

ABSTRACT: RNA pseudoknots play a critical role in RNA-related biology from the assembly of ribosome to the regulation of viral gene expression. A predictive model for pseudoknot structure and stability is essential for understanding and designing RNA structure and function. A previous statistical mechanical theory allows us to treat canonical H-type RNA pseudoknots that contain no intervening loop between the helices (see S. Cao and S.J. Chen [2006] in Nucleic Acids Research, Vol. 34; pp. 2634-2652). Biologically significant RNA pseudoknots often contain interhelix loops. Predicting the structure and stability for such more-general pseudoknots remains an unsolved problem. In the present study, we develop a predictive model for pseudoknots with interhelix loops. The model gives conformational entropy, stability, and the free-energy landscape from RNA sequences. The main features of this new model are the computation of the conformational entropy and folding free-energy base on the complete conformational ensemble and rigorous treatment for the excluded volume effects. Extensive tests for the structural predictions show overall good accuracy with average sensitivity and specificity equal to 0.91 and 0.91, respectively. The theory developed here may be a solid starting point for first-principles modeling of more complex, larger RNAs.

SUBMITTER: Cao S

PROVIDER: S-EPMC2661829 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Predicting structures and stabilities for H-type pseudoknots with interhelix loops.

Cao Song S Chen Shi-Jie SJ

RNA (New York, N.Y.) 20090223 4

RNA pseudoknots play a critical role in RNA-related biology from the assembly of ribosome to the regulation of viral gene expression. A predictive model for pseudoknot structure and stability is essential for understanding and designing RNA structure and function. A previous statistical mechanical theory allows us to treat canonical H-type RNA pseudoknots that contain no intervening loop between the helices (see S. Cao and S.J. Chen [2006] in Nucleic Acids Research, Vol. 34; pp. 2634-2652). Biol ...[more]

PMID: 19237463

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Project description:Comparative protein structure prediction is limited mostly by the errors in alignment and loop modeling. We describe here a new automated modeling technique that significantly improves the accuracy of loop predictions in protein structures. The positions of all nonhydrogen atoms of the loop are optimized in a fixed environment with respect to a pseudo energy function. The energy is a sum of many spatial restraints that include the bond length, bond angle, and improper dihedral angle terms from the CHARMM-22 force field, statistical preferences for the main-chain and side-chain dihedral angles, and statistical preferences for nonbonded atomic contacts that depend on the two atom types, their distance through space, and separation in sequence. The energy function is optimized with the method of conjugate gradients combined with molecular dynamics and simulated annealing. Typically, the predicted loop conformation corresponds to the lowest energy conformation among 500 independent optimizations. Predictions were made for 40 loops of known structure at each length from 1 to 14 residues. The accuracy of loop predictions is evaluated as a function of thoroughness of conformational sampling, loop length, and structural properties of native loops. When accuracy is measured by local superposition of the model on the native loop, 100, 90, and 30% of 4-, 8-, and 12-residue loop predictions, respectively, had <2 A RMSD error for the mainchain N, C(alpha), C, and O atoms; the average accuracies were 0.59 +/- 0.05, 1.16 +/- 0.10, and 2.61 +/- 0.16 A, respectively. To simulate real comparative modeling problems, the method was also evaluated by predicting loops of known structure in only approximately correct environments with errors typical of comparative modeling without misalignment. When the RMSD distortion of the main-chain stem atoms is 2.5 A, the average loop prediction error increased by 180, 25, and 3% for 4-, 8-, and 12-residue loops, respectively. The accuracy of the lowest energy prediction for a given loop can be estimated from the structural variability among a number of low energy predictions. The relative value of the present method is gauged by (1) comparing it with one of the most successful previously described methods, and (2) describing its accuracy in recent blind predictions of protein structure. Finally, it is shown that the average accuracy of prediction is limited primarily by the accuracy of the energy function rather than by the extent of conformational sampling.

Dataset Information

Predicting structures and stabilities for H-type pseudoknots with interhelix loops.

Publications

Predicting structures and stabilities for H-type pseudoknots with interhelix loops.

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