Slipknot or Crystallographic Error: A Computational Analysis of the Plasmodium falciparum DHFR Structural Folds.
Publication Date
2022-01-28Journal Title
Int J Mol Sci
ISSN
1661-6596
Publisher
MDPI AG
Volume
23
Issue
3
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Tata, R. B., Alsulami, A. F., Sheik Amamuddy, O., Blundell, T., & Tastan Bishop, Ö. (2022). Slipknot or Crystallographic Error: A Computational Analysis of the Plasmodium falciparum DHFR Structural Folds.. Int J Mol Sci, 23 (3) https://doi.org/10.3390/ijms23031514
Abstract
The presence of protein structures with atypical folds in the Protein Data Bank (PDB) is rare and may result from naturally occurring knots or crystallographic errors. Proper characterisation of such folds is imperative to understanding the basis of naturally existing knots and correcting crystallographic errors. If left uncorrected, such errors can frustrate downstream experiments that depend on the structures containing them. An atypical fold has been identified in P. falciparum dihydrofolate reductase (PfDHFR) between residues 20-51 (loop 1) and residues 191-205 (loop 2). This enzyme is key to drug discovery efforts in the parasite, necessitating a thorough characterisation of these folds. Using multiple sequence alignments (MSA), a unique insert was identified in loop 1 that exacerbates the appearance of the atypical fold-giving it a slipknot-like topology. However, PfDHFR has not been deposited in the knotted proteins database, and processing its structure failed to identify any knots within its folds. The application of protein homology modelling and molecular dynamics simulations on the DHFR domain of P. falciparum and those of two other organisms (E. coli and M. tuberculosis) that were used as molecular replacement templates in solving the PfDHFR structure revealed plausible unentangled or open conformations of these loops. These results will serve as guides for crystallographic experiments to provide further insights into the atypical folds identified.
Keywords
P. falciparum DHFR, PDB, atypical folds, slipknots, crystallographic error
Sponsorship
Wellcome Trust (107740/Z/15/Z)
National Institutes of Health (U24HG006941)
Identifiers
External DOI: https://doi.org/10.3390/ijms23031514
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333427
Rights
Licence:
https://creativecommons.org/licenses/by/4.0/
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.