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      https://www.ias.ac.in/article/fulltext/jcsc/129/07/1017-1030

    • Keywords

       

      Pore forming toxins; cytolysin A; α-hemolysin; molecular dynamics; MARTINI force-field; membrane protein.

    • Abstract

       

      Pore forming toxins (PFTs) are virulent proteins whose primary goal is to lyse target cells by unregulated pore formation. Molecular dynamics simulations can potentially provide molecular insights on the properties of the pore complex as well as the underlying pathways for pore formation. In this manuscript wecompare both coarse-grained (MARTINI force-field) and all-atom simulations, and comment on the accuracy of the MARTINI coarse-grained method for simulating these large membrane protein pore complexes. We report 20 μs long coarse-grained MARTINI simulations of prototypical pores from two different classes ofpore forming toxins (PFTs) in lipid membranes - Cytolysin A (ClyA), which is an example of an α toxin, and α-hemolysin (AHL) which is an example of a β toxin. We compare and contrast structural attributes such as the root mean square deviation (RMSD) histograms and the inner pore radius profiles from the MARTINIsimulations with all-atom simulations. RMSD histograms sampled by the MARTINI simulations are about a factor of 2 larger, and the radius profiles show that the transmembrane domains of both ClyA and AHL pores undergo significant distortions, when compared with the all-atom simulations. In addition to the fully inserted transmembrane pores, membrane-inserted proteo-lipid ClyA arcs show large shape distortions with a tendency to close in the MARTINI simulations. While this phenomenon could be biologically plausible given the factthat α-toxins can form pores of varying sizes, the additional flexibility is probably due to weaker inter-protomer interactions which are modulated by the elastic dynamic network in the MARTINI force-field. We conclude that there is further scope for refining inter-protomer contacts and perhaps membrane-protein interactions in the MARTINI coarse-grained framework. A robust coarse-grained force-field will enable one to reliably carry out mesoscopic simulations which are required to understand protomer oligomerization, pore formation and leakage.

    • Author Affiliations

       

      RAJAT DESIKAN1 SWARNA M PATRA2 3 KUMAR SARTHAK2 PRABAL K MAITI2 K G AYAPPA1 4

      1. Department of Chemical Engineering, Indian Institute of Science, Bengaluru 560 012, India
      2. Centre for Condensed Matter Theory, Department of Physics, Indian Institute of Science, Bengaluru 560 012, India
      3. Department of Chemistry, R V Engineering College, Mysore Road, Bangalore, Karnataka 560 059, India
      4. Center for Biosystems Science and Engineering, Indian Institute of Science, Bengaluru 560 012, India
    • Dates

       
  • Journal of Chemical Sciences | News

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