Using iterative fragment assembly and progressive sequence truncation to facilitate phasing and crystal structure determination of distantly related proteins

Molecular replacement (MR) often requires templates with high homology to solve the phase problem in X-ray crystallography.I-TASSER-MRhas 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-TASSERgenerated 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-MRfound 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-MRwas also applied to 14 protein targets from structure genomics centers. Seven of these were successfully solved byI-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.

Lexicalization of intensifiers

The present study investigates the lexicalization of zhenshi and shizaishi in Taiwan Mandarin, showing how they originate as a fusion of an adverb and the copula/focus marker shi and further develop a non-compositional meaning through talk-in-interaction and function as right peripheral stance markers in speech. Many instances of the copula/focus marker shi in Modern Mandarin have become a word-internal element and merged with an adverb/conjunction to form an X-shi construction semantically similar to the original X. Our targets, zhenshi and shizaishi, are instantiations of this morphological trend. However, through sequence truncation and metonymic inference, the two morphological fusion cases further demonstrate lexicalization as they respectively acquire an evaluative meaning. Our study thus illustrates the emergent nature of grammar/lexicon arising from the interaction among language (syntagmatic co-occurrence), culture (communicative politeness), and cognition (pragmatic inference).