{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T11:03:15Z","timestamp":1791025395250,"version":"4.1.0"},"reference-count":63,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2013,2,22]],"date-time":"2013-02-22T00:00:00Z","timestamp":1361491200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Various gating modifier toxins partition into membranes and interfere with the gating mechanisms of biological ion channels. For example, GsMTx4 potentiates gramicidin and several bacterial mechanosensitive channels whose gating kinetics are sensitive to mechanical properties of the membrane, whereas binding of HpTx2 shifts the voltage-activity curve of the voltage-gated potassium channel Kv4.2 to the right. The detailed process by which the toxin partitions into membranes has been difficult to probe using molecular dynamics due to the limited time scale accessible. Here we develop a protocol that allows the spontaneous assembly of a polypeptide toxin into membranes in atomistic molecular dynamics simulations of tens of nanoseconds. The protocol is applied to GsMTx4 and HpTx2. Both toxins, released in water at the start of the simulation, spontaneously bind into the lipid bilayer within 50 ns, with their hydrophobic patch penetrated into the bilayer beyond the phosphate groups of the lipids. It is found that the bilayer is about 2 \u00c5 thinner upon the binding of a GsMTx4 monomer. Such a thinning effect of GsMTx4 on membranes may explain its potentiation effect on gramicidin and mechanosensitive channels.<\/jats:p>","DOI":"10.3390\/toxins5020456","type":"journal-article","created":{"date-parts":[[2013,2,22]],"date-time":"2013-02-22T11:21:34Z","timestamp":1361532094000},"page":"456-471","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Effect of Gating Modifier Toxins on Membrane Thickness: Implications for Toxin Effect on Gramicidin and Mechanosensitive Channels"],"prefix":"10.3390","volume":"5","author":[{"given":"Rong","family":"Chen","sequence":"first","affiliation":[{"name":"Research School of Biology, Australian National University, Canberra, ACT 0200, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin-Ho","family":"Chung","sequence":"additional","affiliation":[{"name":"Research School of Biology, Australian National University, Canberra, ACT 0200, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2013,2,22]]},"reference":[{"key":"ref_1","first-page":"919","article-title":"Voltage sensor-trapping: Enhanced activation of sodium channels by \u03b2-scorpion toxin bound to the S3\u2013S4 loop in domain II","volume":"21","author":"Qu","year":"1998","journal-title":"Neuron"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.toxicon.2006.09.022","article-title":"Voltage-gated ion channels and gating modifier toxins","volume":"49","author":"Catterall","year":"2007","journal-title":"Toxicon"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.tips.2009.12.007","article-title":"Targeting voltage sensors in sodium channels with spider toxins","volume":"31","author":"Bosmans","year":"2010","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"191","DOI":"10.3390\/toxins4030191","article-title":"Spider-venom peptides as bioinsecticides","volume":"4","author":"Windley","year":"2012","journal-title":"Toxins"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.toxicon.2006.09.024","article-title":"Tarantula toxins interacting with voltage sensors in potassium channels","volume":"49","author":"Swartz","year":"2007","journal-title":"Toxicon"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1862","DOI":"10.1021\/bi201633j","article-title":"Solution structure of Kurtoxin: A gating modifier selective for Cav3 voltage-gated Ca2+ channels","volume":"51","author":"Lee","year":"2012","journal-title":"Biochemistry"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/j.toxicon.2011.03.017","article-title":"From snake venom toxins to therapeutics\u2014Cardiovascular examples","volume":"59","author":"Koh","year":"2012","journal-title":"Toxicon"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1016\/j.toxicon.2006.11.029","article-title":"Sea anemone venom as a source of insecticidal peptides acting on voltage-gated Na+ channels","volume":"49","author":"Bosmans","year":"2007","journal-title":"Toxicon"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1016\/j.toxicon.2009.02.028","article-title":"Sea anemone toxins affecting voltage-gated sodium channels\u2014Molecular and evolutionary features","volume":"54","author":"Moran","year":"2009","journal-title":"Toxicon"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3881","DOI":"10.1016\/j.febslet.2005.05.077","article-title":"Molecular interaction of \u03b4-conotoxins with voltage-gated sodium channels","volume":"579","author":"Leipold","year":"2005","journal-title":"FEBS Lett."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3916","DOI":"10.1152\/jn.01304.2004","article-title":"Effects of \u03b4-conotoxins PVIA and SVIE on sodium channels in the amphibian sympathetic nervous system","volume":"94","author":"West","year":"2005","journal-title":"J. Neurophysiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1111\/j.1399-3011.1995.tb01068.x","article-title":"Chemical synthesis and characterization of ShK toxin: A potent potassium channel inhibitor from a sea anemone","volume":"46","author":"Pennington","year":"1995","journal-title":"Int. J. Peptide Protein Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1021\/bi00427a049","article-title":"A molluscivorous Conus toxin: Conserved frameworks in conotoxins","volume":"28","author":"Hillyard","year":"1989","journal-title":"Biochemistry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1111\/j.1432-1033.1996.0491r.x","article-title":"Chemical synthesis and characterization of maurotoxin, a short scorpion toxin with four disulfide bridges that acts on K+ channels","volume":"242","author":"Kharrat","year":"1996","journal-title":"Eur. J. Biochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1021\/bi9614390","article-title":"Three-dimensional structure of toxin OSK1 from Orthochirus scrobiculosus scorpion venom","volume":"36","author":"Jaravine","year":"1997","journal-title":"Biochemistry"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.toxicon.2006.09.023","article-title":"Voltage-gated sodium channel modulation by scorpion \u03b1-toxins","volume":"49","author":"Bosmans","year":"2007","journal-title":"Toxicon"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.toxicon.2006.11.015","article-title":"The insecticidal potential of scorpion \u03b2-toxins","volume":"49","author":"Gurevitz","year":"2007","journal-title":"Toxicon"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4796","DOI":"10.1021\/jp300127j","article-title":"Conserved functional surface of anti-mammalian scorpion \u03b2-toxins","volume":"116","author":"Chen","year":"2012","journal-title":"J. Phys. Chem. B"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7775","DOI":"10.1021\/bi300776g","article-title":"Binding modes and functional surface of anti-mammalian scorpion \u03b1-toxins to sodium channels","volume":"51","author":"Chen","year":"2012","journal-title":"Biochemistry"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1046\/j.1432-1327.1999.00726.x","article-title":"Isolation, amino acid sequence and functional assays of SGTx1. The first toxin purified from the venom of the spider scodra griseipes","volume":"265","author":"Marvin","year":"1999","journal-title":"Eur. J. Biochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1016\/0896-6273(95)90184-1","article-title":"An inhibitor of the Kv2.1 potassium channel isolated from the venom of a Chilean tarantula","volume":"15","author":"Swartz","year":"1995","journal-title":"Neuron"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1038\/nature02632","article-title":"A membrane-access mechanism of ion channel inhibition by voltage sensor toxins from spider venom","volume":"430","author":"Lee","year":"2004","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/S0026-895X(24)13491-8","article-title":"Heteropodatoxins: Peptides isolated from spider venom that block Kv4.2 potassium channels","volume":"51","author":"Sanguinetti","year":"1997","journal-title":"Mol. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1021\/bi0353373","article-title":"Solution structure and functional characterization of SGTx1, a modifier of Kv2.1 channel gating","volume":"43","author":"Lee","year":"2004","journal-title":"Biochemistry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.toxicon.2004.11.015","article-title":"Heteropoda toxin 2 is a gating modifier toxin specific for voltage-gated K+ channels of the Kv4 family","volume":"45","author":"Zarayskiy","year":"2005","journal-title":"Toxicon"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1038\/nature06266","article-title":"Portability of paddle motif function and pharmacology in voltage sensors","volume":"450","author":"Alabi","year":"2007","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1085\/jgp.200709869","article-title":"Tarantula toxins interact with voltage sensors within lipid membranes","volume":"130","author":"Milescu","year":"2007","journal-title":"J. Gen. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"L20","DOI":"10.1529\/biophysj.107.112375","article-title":"Is lipid bilayer binding a common property of inhibitor cysteine knot ion-channel blockers?","volume":"93","author":"Posokhov","year":"2007","journal-title":"Biophys. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1038\/nature03873","article-title":"Voltage-sensor activation with a tarantula toxin as cargo","volume":"436","author":"Phillips","year":"2005","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1085\/jgp.115.5.583","article-title":"Identification of a peptide toxin from Grammostola spatulata spider venom that blocks cation-selective stretch-activated channels","volume":"115","author":"Suchyna","year":"2000","journal-title":"J. Gen. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2870","DOI":"10.1016\/j.bpj.2010.09.022","article-title":"Effects of GsMTx4 on bacterial mechanosensitive channels in inside-out patches from giant spheroplasts","volume":"99","author":"Kamaraju","year":"2010","journal-title":"Biophys. J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/nature02743","article-title":"Bilayer-dependent inhibition of mechanosensitive channels by neuroactive peptide enantiomers","volume":"430","author":"Suchyna","year":"2004","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"11844","DOI":"10.1021\/bi061111z","article-title":"Vstx1, a modifier of Kv channel gating, localizes to the interfacial region of lipid bilayers","volume":"45","author":"Bemporad","year":"2006","journal-title":"Biochemistry"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"L07","DOI":"10.1529\/biophysj.106.098681","article-title":"SGTx1, a Kv channel gating-modifier toxin, binds to the interfacial region of lipid bilayers","volume":"92","author":"Wee","year":"2007","journal-title":"Biophys. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3816","DOI":"10.1529\/biophysj.108.130971","article-title":"Lipid bilayer deformation and the free energy of interaction of a Kv channel gating-modifier toxin","volume":"95","author":"Wee","year":"2008","journal-title":"Biophys. J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1021\/ct900652s","article-title":"Membrane\/toxin interaction energetics via serial multiscale molecular dynamics simulations","volume":"6","author":"Wee","year":"2010","journal-title":"J. Chem. Theory Comput."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1007\/s00249-006-0044-z","article-title":"Interaction between K+ channel gate modifier hanatoxin and lipid bilayer membranes analyzed by molecular dynamics simulation","volume":"35","author":"Nishizawa","year":"2006","journal-title":"Eur. Biophys. J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4233","DOI":"10.1529\/biophysj.106.101071","article-title":"Molecular dynamics simulations of a stretch-activated channel inhibitor GsMTx4 with lipid membranes: Two binding modes and effects of lipid structure","volume":"92","author":"Nishizawa","year":"2007","journal-title":"Biophys. J."},{"key":"ref_39","unstructured":"Chen, R. (2011). Effect of External Conditions on Membrane-Protein Interactions. [PhD Thesis, The University of Queensland]."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1016\/j.bpj.2009.12.4321","article-title":"Interactions between a voltage sensor and a toxin via multiscale simulations","volume":"98","author":"Wee","year":"2010","journal-title":"Biophys. J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5710","DOI":"10.1021\/jp076712u","article-title":"Improved sampling for simulations of interfacial membrane proteins: Application of generalized shadow hybrid Monte Carlo to a peptide toxin\/bilayer system","volume":"112","author":"Wee","year":"2008","journal-title":"J. Phys. Chem. B"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1007\/s00249-011-0677-4","article-title":"The effect of membrane curvature on the conformation of antimicrobial peptides: Implications for binding and the mechanism of action","volume":"40","author":"Chen","year":"2011","journal-title":"Eur. Biophys. J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4175","DOI":"10.1021\/ct200316w","article-title":"Statistical convergence of equilibrium properties in simulations of molecular solutes embedded in lipid bilayers","volume":"7","author":"Neale","year":"2011","journal-title":"J. Chem. Theory Comput."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/S0022-2836(83)80007-2","article-title":"Lipid bilayer thickness varies linearly with acyl chain length in fluid phosphatidylcholine vesicles","volume":"166","author":"Lewis","year":"1983","journal-title":"J. Mol. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/nature08542","article-title":"Structure and hydration of membranes embedded with voltage-sensing domains","volume":"462","author":"Krepkiy","year":"2009","journal-title":"Nature"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.bpj.2012.11.3813","article-title":"Membrane-mediated protein-protein interactions and connection to elastic models: A coarse-grained simulation analysis of gramicidin A association","volume":"104","author":"Yoo","year":"2013","journal-title":"Biophys. J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1002\/jcc.21396","article-title":"A new force field for simulating phosphatidylcholine bilayers","volume":"31","author":"Poger","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1007\/s00249-008-0386-9","article-title":"Concentration dependent effect of GsMTx4 on mechanosensitive channels of small conductance in E. coli spheroplasts","volume":"38","author":"Hurst","year":"2009","journal-title":"Eur. Biophys. J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/0005-2736(83)90264-X","article-title":"The effects of bilayer thickness and tension on gramicidin single-channel lifetime","volume":"735","author":"Elliott","year":"1983","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1038\/nature00992","article-title":"Open channel structure of MscL and the gating mechanism of mechanosensitive channels","volume":"418","author":"Perozo","year":"2002","journal-title":"Nature"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.toxicon.2006.09.030","article-title":"Mechanosensitive ion channels and the peptide inhibitor GsMTx-4: History, properties, mechanisms and pharmacology","volume":"49","author":"Bowman","year":"2007","journal-title":"Toxicon"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"6077","DOI":"10.1021\/cr1000783","article-title":"Defect-mediated trafficking across cell membranes: Insights from in silico modeling","volume":"110","author":"Gurtovenko","year":"2010","journal-title":"Chem. Rev."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.bpc.2010.02.018","article-title":"Lipid ion channels","volume":"150","author":"Heimburg","year":"2010","journal-title":"Biophys. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"34443","DOI":"10.1074\/jbc.M202715200","article-title":"Solution structure of peptide toxins that block mechanosensitive ion channels","volume":"277","author":"Oswald","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_55","first-page":"2059","article-title":"Solution structure of HpTX2, a toxin from Heteropoda venatoria spider that blocks Kv4.2 potassium channel","volume":"9","author":"Bernard","year":"2000","journal-title":"Protein Sci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1002\/jcc.20289","article-title":"Scalable molecular dynamics with NAMD","volume":"26","author":"Phillips","year":"2005","journal-title":"J. Comput. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3586","DOI":"10.1021\/jp973084f","article-title":"All-atom empirical potential for molecular modeling and dynamics studies of proteins","volume":"102","author":"MacKerell","year":"1998","journal-title":"J. Phys. Chem. B"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"7830","DOI":"10.1021\/jp101759q","article-title":"Update of the CHARMM all-atom additive force field for lipids: Validation on six lipid types","volume":"114","author":"Klauda","year":"2010","journal-title":"J. Phys. Chem. B"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison of simple potential functions for simulating liquid water","volume":"79","author":"Jorgensen","year":"1982","journal-title":"J. Chem. Phys."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/0021-9991(77)90098-5","article-title":"Numerical integration of the cartesian equations of motion of a system with constraints: Molecular dynamics of n-alkanes","volume":"23","author":"Ryckaert","year":"1977","journal-title":"J. Comput. Phys."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1002\/jcc.540130805","article-title":"SETTLE: An analytical version of the SHAKE and RATTLE algorithm for rigid water models","volume":"13","author":"Miyamoto","year":"1992","journal-title":"J. Comput. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: Visual molecular dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. Graph."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1002\/jcc.540130812","article-title":"The weighted histogram analysis method for free-energy calculations on biomolecules. I. The method","volume":"13","author":"Kumar","year":"1992","journal-title":"J. Comput. Chem."}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/5\/2\/456\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:45:05Z","timestamp":1760219105000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/5\/2\/456"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,2,22]]},"references-count":63,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2013,2]]}},"alternative-id":["toxins5020456"],"URL":"https:\/\/doi.org\/10.3390\/toxins5020456","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,2,22]]}}}