Ab initio protein structure assembly using continuous structure fragments and optimized knowledge-based force field

Abstract

Ab initio protein folding is one of the major unsolved problems in computational biology owing to the difficulties in force field design and conformational search. We developed a novel program, QUARK, for template-free protein structure prediction. Query sequences are first broken into fragments of 1-20 residues where multiple fragment structures are retrieved at each position from unrelated experimental structures. Full-length structure models are then assembled from fragments using replica-exchange Monte Carlo simulations, which are guided by a composite knowledge-based force field. A number of novel energy terms and Monte Carlo movements are introduced and the particular contributions to enhancing the efficiency of both force field and search engine are analyzed in detail. QUARK prediction procedure is depicted and tested on the structure modeling of 145 nonhomologous proteins. Although no global templates are used and all fragments from experimental structures with template modeling score >0.5 are excluded, QUARK can successfully construct 3D models of correct folds in one-third cases of short proteins up to 100 residues. In the ninth community-wide Critical Assessment of protein Structure Prediction experiment, QUARK server outperformed the second and third best servers by 18 and 47% based on the cumulative Z-score of global distance test-total scores in the FM category. Although ab initio protein folding remains a significant challenge, these data demonstrate new progress toward the solution of the most important problem in the field.

Figure 1

(A) Representation of QUARK semi-reduced model where a protein chain conformation is specified by the full backbone atoms and the side-chain center of mass (SC). (B) Conformations of N_i, Cα_i and C_i represented in the Cartesian system. (C) Conformations of N_i, Cα_i and C_i represented in the torsion-angle system, where each atom position is determined by the distance, inner angle and torsion angle relationship to the previous three atoms.

Figure 2

Flowchart of the QUARK ab initio prediction.

Figure 3

Illustrations of distance-specific contact potentials for three atom pairs. (A) Pair-wise backbone Cα-Cα potential. (B) Pair-wise SC-SC potential. (C) Excluded volume potential.

Figure 4

Illustration of solvent accessibility estimation for a residue i based on the distance to its neighboring residues js.

Figure 5

Illustration of eleven movements designed for the QUARK simulations. New conformations after movements are represented by dash lines.

Figure 6

TM-score of the first cluster center model versus the Pearson correlation coefficient of the QUARK energy and the TM-score of decoys. 5,000 decoys have been generated for each protein to calculate the Pearson correlation coefficient.

Figure 7

Three illustrative examples for energy-to-TM-score correlations of 5,000 decoys. The cluster center model (in gray) selected from the decoy set is superimposed onto the native structure (in black). (A) 1b4bA. (B) 2bl7A. (C) 2o42A.

Figure 8

Comparison of the best in top 5 cluster center models by Rosetta and QUARK on 145 test sequences. (A) RMSD. (B) TM-score. (C) HB-score.

Figure 9

Examples of successful modeling results by QUARK in the benchmark set. Experimental structure, QUARK model and Rosetta model are in red, green and blue separately. (A) 2gybT. (B) 1ykuA. (C) 2v94B. (D) 1jo0A.

Figure 10

Examples of QUARK modeling results in CASP9. Experimental structure and QUARK model are in red and green separately. (A) T0547-D3. (B) T0618-D1. (C) T0624-D1. (D) T0529-D1.