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

• Published in: PLoS computational biology 2022-10, Vol.18 (10), p.e1010578-e1010578
• Main Authors: Holmes, Alexandra O. M, Goldman, Adrian, Kalli, Antreas C
• Format: Article
• Language: English
• Subjects: Analysis; Binding sites; Biology and Life Sciences; Helices; Identification and classification; Infectivity; Lipids; Membrane proteins; Membranes; Methods; Molecular dynamics; Parasites; Pathogens; Physical Sciences; Properties; Proteins; Simulation; Structure-function relationships
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1010578

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.