title: Putative membrane lytic sites of P-type and S-type cardiotoxins from snake venoms as probed by all-atom molecular dynamics simulations.
abstract: Cardiotoxins (CTXs) belonging to the three-finger toxin superfamily of snake venoms are one of principal toxic components and the protein toxins exhibit membrane lytic activities when the venoms are injected into victims. In the present study, complex formations between CTX VI (a P-type CTX from Naja atra) and CTX1 (an S-type CTX from Naja naja) on zwitterionic POPC bilayers (a major lipid component of cell membranes) have been studied in near physiological conditions for a total dynamic time scale of 1.35 μs using all-atom molecular dynamics (MD) simulations. Comprehensive analyses of the MD data revealed that residues such as Leu1, Lys2, Tyr11, Lys31, Asp57 and Arg58 of CTX VI, and Ala16, Lys30 and Arg58 of CTX1 were crucial for establishing interactions with the POPC bilayer. Moreover, loop I, along with globular head and loop II of CTX VI, and loop II of CTX1 were found to be the structural regions chiefly governing complex formation of the respective proteins with POPC. Rationalizations for the differential binding modes of CTXs and implications of the findings for designing small molecular inhibitors to the toxins are also discussed. Graphical Abstract Binding modes of a P-type CTX and an S-type CTX towards the POPC bilayer.
authors.affiliation: Structural Biology Lab, Department of Bioinformatics, School of Chemical and Biotechnology, SASTRA University, Thanjavur, 613 401, Tamil Nadu, India.
authors.forename: Biswajit
authors.initials: B
authors.lastname: Gorai
authors.affiliation: Pharmacogenomics and CADD Lab, Department of Bioinformatics, Alagappa University, Karaikudi, 630004, Tamil Nadu, India.
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Karthikeyan
authors.affiliation: Structural Biology Lab, Department of Bioinformatics, School of Chemical and Biotechnology, SASTRA University, Thanjavur, 613 401, Tamil Nadu, India. sivaram@scbt.sastra.edu.
authors.forename: Thirunavukkarasu
authors.initials: T
authors.lastname: Sivaraman
mesh_terms: D000818:Animals; D054715:Cardiotoxins / Q000737:chemistry*; D002462:Cell Membrane / Q000737:chemistry*; D008051:Lipid Bilayers / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D000073176:Naja naja / Q000378:metabolism; D011487:Protein Conformation; D012910:Snake Venoms / Q000737:chemistry*
chemical_list: D054715:Cardiotoxins; D008051:Lipid Bilayers; D012910:Snake Venoms
keywords: Cardiotoxin; Lytic site; Molecular dynamics simulation; POPC bilayer and chemical inhibitor