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Free-binding energies and molecular interac3ons of yessotoxin in the voltage-gated sodium channel Na V 1.5: an in silico approach Several marine dinoflagellates produce unique secondary metabolites with intriguing biological ac3vi3es. Yessotoxin (YTX) and analogs are produced by three species of marine dinoflagellates, with potent ion-channel ac3vity. This study aimed to evaluate the affinity of YTX for the Na V 1.5 channel, using in silico modelling tools. INTRODUCTION Significant interac3ons and low binding free energies (ΔG), between -6.79 and -10.32 Kcal mol -1 for YTX in the Na V 1.5 protein model. Certain amino acid residues in Domains I and II were reached, indica3ng that this toxin is a poten3al Na V 1.5 modulator. MATERIALS AND METHODS Alignment Selec3on Coverage UniProt Q14524 Homo sapiens Sequence search Swiss model h]ps:// swissmodel.expasy.org/ Homology modeling Basic and theorical structure Primary channel structure Func3onal valida3on Model refinement Structural valida3on Characteriza3on & valida3on Molecular Docking Blind docking 126 x 126 x 126 Å Binding free energy AutoDockTools Triplicates Data analysis AutoDock Tools 1.5.6 Conforma3ons Interac3ons Region 1 Region 2 Region 3 Region 4 Region 5 This study cons3tutes the first approach to in silico explora3on of polyke3de-derived dinoflagellate toxins in pursuit of evalua3ng their therapeu3c poten3al. -15 -10 -5 0 Region 1 Region 2 Region 3 Region 4 Region 5 Binding free energy (ΔG Kcal·mol-1) Simula5on regions 0 10 20 30 40 Region 1 Region 2 Region 3 Region 4 Region 5 % cluster Interaction of YTX in DI and DII of Na V 1.5. YTX (pink) and different amino acids (blue) Average ΔG = -10.3 Kcal mol -1 RESULTS What’s next? To understand the effects of YTX on the voltage-gated sodium channel different studies are needed, i.e. electrophysiology and molecular dynamics analyses Thanks to: María del Carmen Osorio-Ramírez 1 , Lorena María Durán- Riveroll 2,3 , Allan D. Cembella 3 , and José Correa-Basurto 1 1 Laboratorio de Diseño y Desarrollo de Nuevos Fármacos e Innovación Biotecnológica, Sección de Estudios de Posgrado e Inves3gación. Escuela Superior de Medicina, Ins3tuto Politécnico Nacional, Ciudad de México, México; 2 CONACyT- Departamento de Biotecnología Marina, Centro de Inves3gación Cientfica y de Educación Superior de Ensenada, Baja California, México; 3 Alfred-Wegener-Ins3tut, Helmholtz-Zentrum für Polar-und Meeresforschung, Bremerhaven, Germany

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Page 1: Free-binding energies and molecular interac3ons of

Free-bindingenergiesandmolecularinterac3onsofyessotoxininthevoltage-gatedsodiumchannelNaV1.5:aninsilicoapproach

Several marine dinoflagellates produce unique secondary metabolites with intriguing biological ac3vi3es.Yessotoxin (YTX) and analogs are produced by three species ofmarine dinoflagellates, with potent ion-channelac3vity.ThisstudyaimedtoevaluatetheaffinityofYTXfortheNaV1.5channel,usinginsilicomodellingtools.

INTRODUCTION

Significant interac3ons and low binding free energies (ΔG), between-6.79and-10.32Kcalmol-1forYTXintheNaV1.5proteinmodel.Certainaminoacid residues inDomains I and IIwere reached, indica3ng thatthistoxinisapoten3alNaV1.5modulator.

MATERIALSANDMETHODS

AlignmentSelec3onCoverage

UniProtQ14524

HomosapiensSequencesearch

Swissmodelh]ps://

swissmodel.expasy.org/

Homologymodeling

Basicandtheoricalstructure

Primarychannelstructure

Func3onalvalida3on

Modelrefinement

Structuralvalida3on

Characteriza3on&valida3on

MolecularDocking

Blinddocking

126x126x126ÅBindingfree

energy

AutoDockToolsTriplicates

Dataanalysis

AutoDockTools1.5.6

Conforma3ons Interac3ons

Region1Region2

Region3Region4

Region5

This study cons3tutes the first approach to in silico explora3on ofpolyke3de-derived dinoflagellate toxins in pursuit of evalua3ng theirtherapeu3cpoten3al.

-15

-10

-5

0Region1 Region2 Region3 Region4 Region5

Bind

ingfreeene

rgy

(ΔGKcal·m

ol-1)

Simula5onregions

010203040

Region1 Region2 Region3 Region4 Region5

%cluster

Interaction of YTX in DI and DII of NaV1.5. YTX (pink) and different amino acids (blue)

AverageΔG=-10.3Kcalmol-1

RESULTS

What’snext?Tounderstand theeffectsofYTXon thevoltage-gatedsodium channel different studies are needed, i.e. electrophysiologyandmoleculardynamicsanalyses

Thanksto:

MaríadelCarmenOsorio-Ramírez1,LorenaMaríaDurán-Riveroll2,3,AllanD.Cembella3,andJoséCorrea-Basurto11LaboratoriodeDiseñoyDesarrollodeNuevosFármacoseInnovaciónBiotecnológica,SeccióndeEstudiosdePosgradoeInves3gación.EscuelaSuperiordeMedicina,Ins3tutoPolitécnicoNacional,CiudaddeMéxico,México;2CONACyT-DepartamentodeBiotecnologíaMarina,CentrodeInves3gaciónCientficaydeEducaciónSuperiordeEnsenada,BajaCalifornia,México;3Alfred-Wegener-Ins3tut,Helmholtz-ZentrumfürPolar-undMeeresforschung,Bremerhaven,Germany

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