title: Using iterative fragment assembly and progressive sequence truncation to facilitate phasing and crystal structure determination of distantly related proteins.
abstract: Molecular replacement (MR) often requires templates with high homology to solve the phase problem in X-ray crystallography. I-TASSER-MR has been developed to test whether the success rate for structure determination of distant-homology proteins could be improved by a combination of iterative fragmental structure-assembly simulations with progressive sequence truncation designed to trim regions with high variation. The pipeline was tested on two independent protein sets consisting of 61 proteins from CASP8 and 100 high-resolution proteins from the PDB. After excluding homologous templates, I-TASSER generated full-length models with an average TM-score of 0.773, which is 12% higher than the best threading templates. Using these as search models, I-TASSER-MR found correct MR solutions for 95 of 161 targets as judged by having a TFZ of >8 or with the final structure closer to the native than the initial search models. The success rate was 16% higher than when using the best threading templates. I-TASSER-MR was also applied to 14 protein targets from structure genomics centers. Seven of these were successfully solved by I-TASSER-MR. These results confirm that advanced structure assembly and progressive structural editing can significantly improve the success rate of MR for targets with distant homology to proteins of known structure.
authors.affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jouko
authors.initials: J
authors.lastname: Virtanen
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Xue
authors.affiliation: Departments of Pharmacology and Biological Chemistry, University of Michigan, Ann Arbor, MI 41809, USA.
authors.forename: John J G
authors.initials: JJ
authors.lastname: Tesmer
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000465:Algorithms; D000818:Animals; D018360:Crystallography, X-Ray / Q000379:methods*; D030562:Databases, Protein; D006801:Humans; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*; D012984:Software
chemical_list: D011506:Proteins
keywords: I-TASSER; X-ray crystallography; molecular replacement; protein structure prediction; threading