Publication Details |
Reference Category | Journals |
DOI / URL | link |
Document | author version |
Title (Primary) | Protein structure prediction guided by crosslinking restraints – A systematic evaluation of the impact of the crosslinking spacer length |
Author | Hofmann, T.; Fischer, A.W.; Meiler, J.; Kalkhof, S. |
Journal | Methods |
Year | 2015 |
Department | PROTEOM |
Volume | 89 |
Page From | 79 |
Page To | 90 |
Language | englisch |
Keywords | Crosslinking; Protein structure prediction; De novo folding; Mass spectrometry; Protein modeling |
UFZ wide themes | RU3; |
Abstract | Recent development of high-resolution mass spectrometry (MS) instruments enables chemical crosslinking (XL) to become a high-throughput method for obtaining structural information about proteins. Restraints derived from XL-MS experiments have been used successfully for structure refinement and protein–protein docking. However, one formidable question is under which circumstances XL-MS data might be sufficient to determine a protein’s tertiary structure de novo? Answering this question will not only include understanding the impact of XL-MS data on sampling and scoring within a de novo protein structure prediction algorithm, it must also determine an optimal crosslinker type and length for protein structure determination. While a longer crosslinker will yield more restraints, the value of each restraint for protein structure prediction decreases as the restraint is consistent with a larger conformational space. In this study, the number of crosslinks and their discriminative power was systematically analyzed in silico on a set of 2055 non-redundant protein folds considering Lys–Lys, Lys–Asp, Lys–Glu, Cys–Cys, and Arg–Arg reactive crosslinkers between 1 and 60 Å. Depending on the protein size a heuristic was developed that determines the optimal crosslinker length. Next, simulated restraints of variable length were used to de novo predict the tertiary structure of fifteen proteins using the BCL::Fold algorithm. The results demonstrate that a distinct crosslinker length exists for which information content for de novo protein structure prediction is maximized. The sampling accuracy improves on average by 1.0 Å and up to 2.2 Å in the most prominent example. XL-MS restraints enable consistently an improved selection of native-like models with an average enrichment of 2.1. |
Persistent UFZ Identifier | https://www.ufz.de/index.php?en=20939&ufzPublicationIdentifier=16181 |
Hofmann, T., Fischer, A.W., Meiler, J., Kalkhof, S. (2015): Protein structure prediction guided by crosslinking restraints – A systematic evaluation of the impact of the crosslinking spacer length Methods 89 , 79 - 90 |