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Cited by 3Lipid Membrane Structure and BehaviorProtein Structure and DynamicsATP Synthase and ATPases Research

The DOI matches its Crossref record; 75 of the 75 references it cites were found in a registry or an index.

mPPases create a conserved anionic membrane fingerprint as identified via multi-scale simulations

Open access
Holmes, Alexandra O. M., Goldman, Adrian, Kalli, Antreas C.·2022·PLOS Computational Biology
DOI 10.1371/journal.pcbi.1010578PMC PMC9560603

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Abstract

Membrane-integral pyrophosphatases (mPPases) are membrane-bound enzymes responsible for hydrolysing inorganic pyrophosphate and translocating a cation across the membrane. Their function is essential for the infectivity of clinically relevant protozoan parasites and plant maturation. Recent developments have indicated that their mechanism is more complicated than previously thought and that the membrane environment may be important for their function. In this work, we use multiscale molecular dynamics simulations to demonstrate for the first time that mPPases form specific anionic lipid interactions at 4 sites at the distal and interfacial regions of the protein. These interactions are conserved in simulations of the mPPases from Thermotoga maritima , Vigna radiata and Clostridium leptum and characterised by interactions with positive residues on helices 1, 2, 3 and 4 for the distal site, or 9, 10, 13 and 14 for the interfacial site. Due to the importance of these helices in protein stability and function, these lipid interactions may play a crucial role in the mPPase mechanism and enable future structural and functional studies.

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Crossref · 10.1371/journal.pcbi.1010578

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Figures

Fig 1 The structure of Tm-PPase and simulation box set up. A) the Tm-PPase resting state crystal structure (PDB: 4AV3) viewed from above to demonstrate the concentric circles of TMH of each subunit (outer ring in cyan and inner in pink) and the TMH contributing to the interface with the adjoining subunit (grey surface representation). B) The atomistic simulation box where the protein subunits are each coloured in cyan and pink and shown as Cartoon representation, the POPE (80%) and POPA (20%) bilayer is shown as lines representation and the water particles are grey points, and the ions (NaCl 150 mM) are shown as yellow VDW particles.
Fig 1 The structure of Tm-PPase and simulation box set up. A) the Tm-PPase resting state crystal structure (PDB: 4AV3) viewed from above to demonstrate the concentric circles of TMH of each subunit (outer ring in cyan and inner in pink) and the TMH contributing to the interface with the adjoining subunit (grey surface representation). B) The atomistic simulation box where the protein subunits are each coloured in cyan and pink and shown as Cartoon representation, the POPE (80%) and POPA (20%) bilayer is shown as lines representation and the water particles are grey points, and the ions (NaCl 150 mM) are shown as yellow VDW particles.CC BY · PubMed Central
Fig 2 Tm-PPase interacts preferentially with anionic lipids at four distinct sites. The contacts between the lipid bilayer and Tm-PPase for model bilayers consisting of 80% POPE and 20% anionic lipid represented by A) normalised lipid contacts with both POPE and POPA/G/S and the residue number of the protein, B) the density of the PO4 bead of the CG anionic lipid around the protein, where the trajectory has been fitted to the protein backbone and C) the contacts of the PO4 atom represented on the 3D structure of the protein with a colour scale from white to green, for POPA, D-F) blue for POPG, and G-I) red for POPS. The lipid contacts were normalised by dividing the number of contacts of each residue with the length of simulation and the number of lipid species.
Fig 2 Tm-PPase interacts preferentially with anionic lipids at four distinct sites. The contacts between the lipid bilayer and Tm-PPase for model bilayers consisting of 80% POPE and 20% anionic lipid represented by A) normalised lipid contacts with both POPE and POPA/G/S and the residue number of the protein, B) the density of the PO4 bead of the CG anionic lipid around the protein, where the trajectory has been fitted to the protein backbone and C) the contacts of the PO4 atom represented on the 3D structure of the protein with a colour scale from white to green, for POPA, D-F) blue for POPG, and G-I) red for POPS. The lipid contacts were normalised by dividing the number of contacts of each residue with the length of simulation and the number of lipid species.CC BY · PubMed Central
Fig 3 Vr-PPase in its native bilayer forms an anionic membrane fingerprint. The interactions between Vr-PPase and a realistic tonoplast membrane represented through A) the average density of the phosphate particles of the anionic lipids (PIP2, POPG, POPS and POPA) calculated using a combined trajectory fitted around the protein, B) the normalised number of contacts between the lipids in the bilayer and the residues of the protein, alongside C) a representation of the contacts on the 3D protein structure of PIP2 (orange) and POPA (green).
Fig 3 Vr-PPase in its native bilayer forms an anionic membrane fingerprint. The interactions between Vr-PPase and a realistic tonoplast membrane represented through A) the average density of the phosphate particles of the anionic lipids (PIP2, POPG, POPS and POPA) calculated using a combined trajectory fitted around the protein, B) the normalised number of contacts between the lipids in the bilayer and the residues of the protein, alongside C) a representation of the contacts on the 3D protein structure of PIP2 (orange) and POPA (green).CC BY · PubMed Central
Fig 4 Electrostatic profiles and arrangements of the mPPases lipid binding sites. The electrostatic profile as calculated by APBS and structural arrangement of the A-B) Tm-PPase, C-D) Vr-PPase and E-F) Cp-PPase protein interfacial anionic lipid binding site with POPA (green sticks) or PIP2 in the case of Vr-PPase bound and the interacting lysines or arginines shown as sticks. The snapshots are the final frame of one of the CG simulations (at 5 μs of simulation) converted to an atomistic representation. G) The distal interaction site of Tm-PPase, and H) the arrangement of a DM detergent molecule (green sticks) in the crystal structure of Vr-PPase (PDB: 4A01).
Fig 4 Electrostatic profiles and arrangements of the mPPases lipid binding sites. The electrostatic profile as calculated by APBS and structural arrangement of the A-B) Tm-PPase, C-D) Vr-PPase and E-F) Cp-PPase protein interfacial anionic lipid binding site with POPA (green sticks) or PIP2 in the case of Vr-PPase bound and the interacting lysines or arginines shown as sticks. The snapshots are the final frame of one of the CG simulations (at 5 μs of simulation) converted to an atomistic representation. G) The distal interaction site of Tm-PPase, and H) the arrangement of a DM detergent molecule (green sticks) in the crystal structure of Vr-PPase (PDB: 4A01).CC BY · PubMed Central

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Cites

Show all 75 references

Research works printed but not linked: 1

  1. W. DeLano, 2002, Pymol: An Open-Source Molecular Graphics Tool, CCP4 Newsl Protein Crystallogr, 40

Metadata

Authors
Holmes, A. O. M., Goldman, A., & Kalli, A. C.
Affiliations
University of Leeds (GB)
Corresponding author
Kalli, Antreas C.
ORCID
Venue
PLOS Computational Biology
Publisher
Public Library of Science (PLoS)
Published
2022-10-03
Volume
18
Issue
10
Pages
e1010578
ISSN
  • 1553-734X (ISSN-L)
  • 1553-7358
DOI
10.1371/journal.pcbi.1010578
PMC
PMC9560603
OpenAlex
W4300689053
Cited by
3
References
75
Citations by year
2024: 3
FWCI
0.24
Type
journal article
Language
en
Update notices
new_version (2022-10-13)
Open access
Licence
Locations
  • PLoS Computational Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Työväentutkimus Vuosikirja (submittedVersion)
Funders
  • Biotechnology and Biological Sciences Research Council (BB/M011151/1, BB/T006048/1)
  • Academy of Finland (1322609)
  • Engineering and Physical Sciences Research Council (EP/R029407/1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
Keywords
protein-lipid interactions, membrane environment, pyrophosphate hydrolysis, cation transport, Thermotoga maritima, mungbean, Clostridium leptum, protozoan parasites, plant maturation, enzyme mechanism
MeSH terms
Cations, Cell Membrane, Lipids, Pyrophosphatases, Diphosphates

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CoChat. (2026). Citation check: mPPases create a conserved anionic membrane fingerprint as identified via multi-scale simulations. https://app.cochat.ai/papers/10.1371/journal.pcbi.1010578
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Holmes, A. O. M., Goldman, A., & Kalli, A. C. (2022). mPPases create a conserved anionic membrane fingerprint as identified via multi-scale simulations. PLOS Computational Biology. https://doi.org/10.1371/journal.pcbi.1010578

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