Use of the UNRES force field in template-assisted prediction of protein structures and the refinement of server models: Test with CASP12 targets
Graphical abstract
Introduction
Prediction of protein structure from amino-acid sequence still remains a major challenge of structural biology, because of still insufficient supply of experimental structures and because the methods developed do not provide sufficiently accurate structures in all situations [1]. While knowledge-based methods, which are largely based on sequence-structure similarity, perform well when good templates with sufficiently similar sequences can be found in structural databases, their reliability decreases dramatically with decreasing sequence similarity. The biannual Critical Assessment of Techniques for Protein Structure Prediction (CASP) experiments [2] demonstrate that there are about 10% of targets for which none of the methods available provides a structure close enough to the experimental structure. The physics-based approaches, which are based on finding the structures with the lowest free energy given an appropriate force field and conformational-search method and are, therefore, not database-dependent, could be expected to handle the cases that are not covered by knowledge-based approaches but the existing force fields are not yet sufficiently accurate.
In our recent work [3,4] we proposed a hybrid approach, which combines the best features of the knowledge-based and physics-based methodology. The approach starts from selecting top models from selected servers, which are then converted into distance- and angle-restraints and, subsequently, large-scale multiplexed replica-exchange molecular dynamics (MREMD) [5] simulations with the physics-based coarse-grained UNRES force field (ref 6 and references therein) are carried out. UNRES applied in ab initio mode has already proved to be good in predicting protein structures, scoring considerable success in the past CASP exercises [7,8]. In particular, it was found that UNRES can predict correct domain packing, resulting in models better in overall topology than those found by template-based methods even for targets of the template-based category [7]. Therefore, in our recent work [4], we proposed an approach in which restraints are imposed only on those fragments of the structure that are similar in all server models; in particular, domain packing is unrestrained in this procedure. This fragment-based approach is new compared to those applied in, e.g., MODELLER [9] or MULTICOM [10], in which restraints derived from whole models are imposed. When the models are diverse in general but share common fragments, it can be expected that the structures of these fragments are predicted with much higher confidence in general than the arrangement of these fragments and the rest of the structure. Therefore, it seems reasonable to impose restraints on the common fragments only. Use of a coarse-grained force field is of advantage in this regard because of lower cost of energy and force evaluation and more extensive search of the conformational space, owing to the reduction of the number of degrees of freedom, even though details of the structure are lost. The test results with CASP11 targets suggested that such an approach gives much better results compared to imposing restraints on whole structures. In this work, we tested the approach in the CASP12 experiment, obtaining a number of very good predictions, two of which (for targets T0892 and T0942) were first-ranked and 80% of models being in the upper 50% of models. Apart from the regular prediction (“T0” type targets) category, our KIAS-Gdansk group also participated in the refinement, oligomer, and data-assisted predictions. Our performance in the data-assisted prediction category has been published as a separate paper [11], while this paper reports our results obtained in the regular, refinement, and oligomer prediction category.
Section snippets
Overview of the prediction protocol
The procedure developed in our earlier work [3,4] is illustrated in Fig. 1. The protocol starts from selecting server models to derive the restraints. As mentioned in the Introduction, only the fragments of the structure that are similar to all server models are restrained. As can be seen from Fig. 1, we used models from only the four servers that were top-performing servers in CASP11. This choice was motivated by our previous work [4], according to which the quality of the models to derive
Results
In this section we describe the performance of the KIAS-Gdansk group in the regular 3D prediction (single-chain “T0” type targets), refinement (“TR” type targets), and oligomer prediction categories. The rankings, the measures of model quality, as well as the GDT_TS plots were taken from the official CASP12 page (http://predictioncenter.org/casp12/index.cgi).
Discussion and conclusions
The purpose of our participation in the CASP12 exercise was to assess the performance and the added value of our structure-prediction methods, in which we use geometric restraints from the BAKER-ROSETTASERVR, GOAL, Zhang-server and QUARK server models. As demonstrated in section Comparison of the KIAS-Gdansk models with the parent server models, our method eliminates the information from the poorest ‘Model 1’ server predictions with about 70% confidence. Given the fact that the four servers
Acknowledgments
This work was supported by grants DEC-2013/10/M/ST4/00640 and DEC-2015/17/N/ST4/03937 from the National Science Center of Poland (Narodowe Centrum Nauki). KJ and JL were supported by the National Research Foundation of Korea grant funded by the Korea government (MEST) (No. 2008-0061987). Calculations were carried out using the computational resources provided by (a) the supercomputer resources at the Informatics Center of the Metropolitan Academic Network (CI TASK) in Gdańsk, (b) the
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