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Slipknot or Crystallographic Error: A Computational Analysis of the Plasmodium falciparum DHFR Structural Folds.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Alsulami, Ali F 
Sheik Amamuddy, Olivier  ORCID logo  https://orcid.org/0000-0002-1781-1382
Blundell, Tom L 
Tastan Bishop, Özlem  ORCID logo  https://orcid.org/0000-0001-6861-7849

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.

Description

Keywords

P. falciparum DHFR, PDB, atypical folds, crystallographic error, slipknots, Crystallography, X-Ray, Databases, Protein, Models, Molecular, Molecular Dynamics Simulation, Plasmodium falciparum, Protein Conformation, Protein Domains, Protein Folding, Protozoan Proteins, Sequence Alignment, Sequence Analysis, Protein, Sequence Homology, Amino Acid, Tetrahydrofolate Dehydrogenase

Journal Title

Int J Mol Sci

Conference Name

Journal ISSN

1661-6596
1422-0067

Volume Title

23

Publisher

MDPI AG
Sponsorship
NIH HHS (U24HG006941)
Wellcome Trust (107740/Z/15/Z)