Slipknot or Crystallographic Error: A Computational Analysis of the <i>Plasmodium falciparum</i> DHFR Structural Folds
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 crystallog...
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MDPI AG
2022-01-01
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| Series: | International Journal of Molecular Sciences |
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| author | Rolland B. Tata Ali F. Alsulami Olivier Sheik Amamuddy Tom L. Blundell Özlem Tastan Bishop |
| author_facet | Rolland B. Tata Ali F. Alsulami Olivier Sheik Amamuddy Tom L. Blundell Özlem Tastan Bishop |
| author_sort | Rolland B. Tata |
| collection | DOAJ |
| description | 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 <i>P. falciparum</i> dihydrofolate reductase (<i>Pf</i>DHFR) 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, <i>Pf</i>DHFR 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 <i>P. falciparum</i> and those of two other organisms (<i>E. coli</i> and <i>M. tuberculosis</i>) that were used as molecular replacement templates in solving the <i>Pf</i>DHFR 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. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:46:45Z |
| publishDate | 2022-01-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-69ba8983783b47c1b79ac45023bec64c2023-11-23T16:41:47ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-01-01233151410.3390/ijms23031514Slipknot or Crystallographic Error: A Computational Analysis of the <i>Plasmodium falciparum</i> DHFR Structural FoldsRolland B. Tata0Ali F. Alsulami1Olivier Sheik Amamuddy2Tom L. Blundell3Özlem Tastan Bishop4Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown 6140, South AfricaDepartment of Biochemistry, Sanger Building, University of Cambridge, Tennis Court Rd., Cambridge CB2 1GA, UKResearch Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown 6140, South AfricaDepartment of Biochemistry, Sanger Building, University of Cambridge, Tennis Court Rd., Cambridge CB2 1GA, UKResearch Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown 6140, South AfricaThe 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 <i>P. falciparum</i> dihydrofolate reductase (<i>Pf</i>DHFR) 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, <i>Pf</i>DHFR 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 <i>P. falciparum</i> and those of two other organisms (<i>E. coli</i> and <i>M. tuberculosis</i>) that were used as molecular replacement templates in solving the <i>Pf</i>DHFR 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.https://www.mdpi.com/1422-0067/23/3/1514<i>P. falciparum</i> DHFRPDBatypical foldsslipknotscrystallographic error |
| spellingShingle | Rolland B. Tata Ali F. Alsulami Olivier Sheik Amamuddy Tom L. Blundell Özlem Tastan Bishop Slipknot or Crystallographic Error: A Computational Analysis of the <i>Plasmodium falciparum</i> DHFR Structural Folds International Journal of Molecular Sciences <i>P. falciparum</i> DHFR PDB atypical folds slipknots crystallographic error |
| title | Slipknot or Crystallographic Error: A Computational Analysis of the <i>Plasmodium falciparum</i> DHFR Structural Folds |
| title_full | Slipknot or Crystallographic Error: A Computational Analysis of the <i>Plasmodium falciparum</i> DHFR Structural Folds |
| title_fullStr | Slipknot or Crystallographic Error: A Computational Analysis of the <i>Plasmodium falciparum</i> DHFR Structural Folds |
| title_full_unstemmed | Slipknot or Crystallographic Error: A Computational Analysis of the <i>Plasmodium falciparum</i> DHFR Structural Folds |
| title_short | Slipknot or Crystallographic Error: A Computational Analysis of the <i>Plasmodium falciparum</i> DHFR Structural Folds |
| title_sort | slipknot or crystallographic error a computational analysis of the i plasmodium falciparum i dhfr structural folds |
| topic | <i>P. falciparum</i> DHFR PDB atypical folds slipknots crystallographic error |
| url | https://www.mdpi.com/1422-0067/23/3/1514 |
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