title: Use of Restraints from Consensus Fragments of Multiple Server Models To Enhance Protein-Structure Prediction Capability of the UNRES Force Field.
abstract: Recently, we developed a new approach to protein-structure prediction, which combines template-based modeling with the physics-based coarse-grained UNited RESidue (UNRES) force field. In this approach, restrained multiplexed replica exchange molecular dynamics simulations with UNRES, with the Cα-distance and virtual-bond-dihedral-angle restraints derived from knowledge-based models are carried out. In this work, we report a test of this approach in the 11th Community Wide Experiment on the Critical Assessment of Techniques for Protein Structure Prediction (CASP11), in which we used the template-based models from early-stage predictions by the LEE group CASP11 server (group 038, called "nns"), and further improvement of the method. The quality of the models obtained in CASP11 was better than that resulting from unrestrained UNRES simulations; however, the obtained models were generally worse than the final nns models. Calculations with the final nns models, performed after CASP11, resulted in substantial improvement, especially for multi-domain proteins. Based on these results, we modified the procedure by deriving restraints from models from multiple servers, in this study the four top-performing servers in CASP11 (nns, BAKER-ROSETTASERVER, Zhang-server, and QUARK), and implementing either all restraints or only the restraints on the fragments that appear similar in the majority of models (the consensus fragments), outlier models discarded. Tests with 29 CASP11 human-prediction targets with length less than 400 amino-acid residues demonstrated that the consensus-fragment approach gave better results, i.e., lower α-carbon root-mean-square deviation from the experimental structures, higher template modeling score, and global distance test total score values than the best of the parent server models. Apart from global improvement (repacking and improving the orientation of domains and other substructures), improvement was also reached for template-based modeling targets, indicating that the approach has refinement capacity. Therefore, the consensus-fragment analysis is able to remove lower-quality models and poor-quality parts of the models without knowing the experimental structure.
authors.affiliation: Faculty of Chemistry, University of Gdańsk , Wita Stwosza 63, 80-308 Gdańsk, Poland.
authors.forename: Magdalena A
authors.initials: MA
authors.lastname: Mozolewska
authors.affiliation: Faculty of Chemistry, University of Gdańsk , Wita Stwosza 63, 80-308 Gdańsk, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Krupa
authors.affiliation: Faculty of Chemistry, University of Gdańsk , Wita Stwosza 63, 80-308 Gdańsk, Poland.
authors.forename: Bartłomiej
authors.initials: B
authors.lastname: Zaborowski
authors.affiliation: Faculty of Chemistry, University of Gdańsk , Wita Stwosza 63, 80-308 Gdańsk, Poland.|Center for In Silico Protein Structure and School of Computational Sciences, Korea Institute for Advanced Study , 85 Hoegiro, Dongdaemun-gu, Seoul 130-722, Republic of Korea.
authors.forename: Adam
authors.initials: A
authors.lastname: Liwo
authors.affiliation: Center for In Silico Protein Structure and School of Computational Sciences, Korea Institute for Advanced Study , 85 Hoegiro, Dongdaemun-gu, Seoul 130-722, Republic of Korea.
authors.forename: Jooyoung
authors.initials: J
authors.lastname: Lee
authors.affiliation: Center for Advanced Computation, Korea Institute for Advanced Study , 85 Hoegiro, Dongdaemun-gu, Seoul 130-722, Republic of Korea.
authors.forename: Keehyoung
authors.initials: K
authors.lastname: Joo
authors.affiliation: Faculty of Chemistry, University of Gdańsk , Wita Stwosza 63, 80-308 Gdańsk, Poland.
authors.forename: Cezary
authors.initials: C
authors.lastname: Czaplewski
mesh_terms: D020169:Caspases / Q000737:chemistry*; D016384:Consensus Sequence; D006801:Humans; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry*; D011487:Protein Conformation
chemical_list: D010446:Peptide Fragments; D020169:Caspases