1. ABOUT THE DATASET
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Title:	

Creator(s): Emma Brown [1], Antreas Kalli [1]]

Organisation(s): 1. University of Leeds.

Rights-holder(s):Unless otherwise stated, Copyright 2023 University of Leeds

Publication Year: 2024

Description: Flaviviruses, including Zika virus (ZIKV), are a significant global health concern, yet no licensed antivirals exist to treat disease. The small Membrane (M) protein plays well-defined roles during viral egress and remains within virion membranes following release and maturation. However, it is unclear whether M plays a functional role in this setting. Here, we show that M forms oligomeric membrane-permeabilising channels in vitro, with increased activity at acidic pH and sensitivity to the prototypic channel-blocker, rimantadine. Accordingly, rimantadine blocked an early stage of ZIKV cell culture infection. Structure-based channel models, comprising hexameric arrangements of two trans-membrane domain protomers were shown to comprise more stable assemblages than other oligomers using molecular dynamics (MD) simulations. Models contained a predicted lumenal rimantadine binding site, as well as a second druggable target region on the membrane-exposed periphery. In silico screening enriched for repurposed drugs/compounds predicted to bind to either one site or the other. Hits displayed superior potency in vitro and in cell culture compared with rimantadine, with efficacy demonstrably linked to virion-resident channels. Finally, rimantadine effectively blocked ZIKV viraemia in preclinical models, supporting that M constitutes a physiologically relevant target. This could be explored by repurposing rimantadine, or development of new M-targeted-therapies.

Cite as: Brown E and Kalli AC, 2024: Inhibitors of the Small Membrane (M) Protein Viroporin Prevent Zika Virus Infection - dataset. University of Leeds. https://doi.org/10.5518/1505  

Related publication: Brown et al.; Inhibitors of the Small Membrane (M) Protein Viroporin Prevent Zika Virus Infection, 2024, eLife

Contact: a.kalli@leeds.ac.uk


2. TERMS OF USE
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Unless otherwise stated, this dataset is licensed under a Creative Commons Attribution 4.0 International Licence: https://creativecommons.org/licenses/by/4.0/.


3. PROJECT AND FUNDING INFORMATION
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Simulations were undertaken on ARC3 and ARC4, part of the High-Performance Computing facilities at the University of Leeds. Work was supported by Institute PhD Scholarships from the Leeds Institute of Medical Research, University of Leeds, (EB and DF: awarded to SG, CM, AK, and RF), Medical Research Council grant G0700124 (S.G.), and Medical Research Council grants (MC_UU_12014/8 and MR/N017552/1) (A.K.).


4. CONTENTS
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In all files below the protein numbering is continues starting from 1. 

final_snap.hexamer_compact_hel3_protonated-1.gro	Final snapshot from the simulation with the Hexamer protonated compact model with Helix 3 facing the channel pore 
final_snap.hexamer_compact_hel3_protonated-2.gro	Final snapshot from the simulation with the Hexamer protonated compact model with Helix 3 facing the channel pore 
final_snap.hexamer_compact_hel3_protonated-3.gro	Final snapshot from the simulation with the Hexamer protonated compact model with Helix 3 facing the channel pore 
final_snap.hexamer_compact_hel3-1.gro	Final snapshot from the simulation with the Hexamer  compact model with Helix 3 facing the channel pore 
final_snap.hexamer_compact_hel3-2.gro	Final snapshot from the simulation with the Hexamer  compact model with Helix 3 facing the channel pore 
final_snap.hexamer_compact_hel3-3.gro	Final snapshot from the simulation with the Hexamer  compact model with Helix 3 facing the channel pore 
final_snap.hexamer_radial_hel3-1.gro	Final snapshot from the simulation with the Hexamer  radial model with Helix 3 facing the channel pore 
final_snap.hexamer_radial_hel3-2.gro	Final snapshot from the simulation with the Hexamer  radial model with Helix 3 facing the channel pore 
final_snap.hexamer_radial_hel3-3.gro	Final snapshot from the simulation with the Hexamer  radial model with Helix 3 facing the channel pore 
final.Zika_EM-1_skip.gro	Final snapshot from the simulation with the Zika monomer taken from the published EM structure  
final.Zika_EM-2_skip.gro	Final snapshot from the simulation with the Zika monomer taken from the published EM structure  
final.Zika_EM-3_skip.gro	Final snapshot from the simulation with the Zika monomer taken from the published EM structure  
final.Zika_EM-4_skip.gro	Final snapshot from the simulation with the Zika monomer taken from the published EM structure  
final.Zika_EM-5_skip.gro	Final snapshot from the simulation with the Zika monomer taken from the published EM structure  
final.Zika_Helix_str-1.gro	Final snapshot from the simulation with the Zika monomer in which the helices are in a straight conformation  
final.Zika_Helix_str-2.gro	Final snapshot from the simulation with the Zika monomer in which the helices are in a straight conformation  
final.Zika_Helix_str-3.gro	Final snapshot from the simulation with the Zika monomer in which the helices are in a straight conformation  
final.Zika_Helix_str-4.gro	Final snapshot from the simulation with the Zika monomer in which the helices are in a straight conformation  
final.Zika_Helix_str-5.gro	Final snapshot from the simulation with the Zika monomer in which the helices are in a straight conformation  
Heptamer_Hel2_compact_t=0ns.gro	Initial snapshot with a heptameric compact structure  of the chanel with Helix 2 facing the channel pore 
Heptamer_Hel2_compact_t=200ns-1.gro	Final snapshot with a heptameric compact structure  of the chanel with Helix 2 facing the channel pore 
Heptamer_Hel2_compact_t=200ns-2.gro	Final snapshot with a heptameric compact structure  of the chanel with Helix 2 facing the channel pore 
Heptamer_Hel2_compact_t=200ns-3.gro	Final snapshot with a heptameric compact structure  of the chanel with Helix 2 facing the channel pore 
Heptamer_Hel2_radial_t=0ns.gro	Initial snapshot with a heptameric radial structure  of the chanel with Helix 2 facing the channel pore 
Heptamer_Hel2_radial_t=200ns-1.gro	Final snapshot with a heptameric radial structure  of the chanel with Helix 2 facing the channel pore 
Heptamer_Hel2_radial_t=200ns-2.gro	Final snapshot with a heptameric radial structure  of the chanel with Helix 2 facing the channel pore 
Heptamer_Hel2_radial_t=200ns-3.gro	Final snapshot with a heptameric radial structure  of the chanel with Helix 2 facing the channel pore 
Heptamer_Hel3_compact_t=0ns.gro	Initial snapshot with a heptameric compact structure  of the chanel with Helix 3 facing the channel pore 
Heptamer_Hel3_compact_t=200ns-1.gro	Final snapshot with a heptameric compact structure  of the chanel with Helix 3 facing the channel pore 
Heptamer_Hel3_compact_t=200ns-2.gro	Final snapshot with a heptameric compact structure  of the chanel with Helix 3 facing the channel pore 
Heptamer_Hel3_compact_t=200ns-3.gro	Final snapshot with a heptameric compact structure  of the chanel with Helix 3 facing the channel pore 
Heptamer_Hel3_radial_t=0ns.gro	Initial snapshot with a heptameric radial structure  of the chanel with Helix 3 facing the channel pore 
Heptamer_Hel3_radial_t=200ns-1.gro	Final snapshot with a heptameric radial structure  of the chanel with Helix 3 facing the channel pore 
Heptamer_Hel3_radial_t=200ns-2.gro	Final snapshot with a heptameric radial structure  of the chanel with Helix 3 facing the channel pore 
Heptamer_Hel3_radial_t=200ns-3.gro	Final snapshot with a heptameric radial structure  of the chanel with Helix 3 facing the channel pore 
Hexamer_compact-hel2_t=0ns.gro	Initial snapshot with a heptameric compact structure  of the chanel with Helix 2 facing the channel pore 
Hexamer_compact-hel2_t=200ns-1.gro	Final snapshot with a heptameric compact structure  of the chanel with Helix 2 facing the channel pore 
Hexamer_compact-hel2_t=200ns-2.gro	Final snapshot with a heptameric compact structure  of the chanel with Helix 2 facing the channel pore 
Hexamer_compact-hel2_t=200ns-3.gro	Final snapshot with a heptameric compact structure  of the chanel with Helix 2 facing the channel pore 
Hexamer_radial-hel2_t=0ns.gro	Initial snapshot with a heptameric radial structure  of the chanel with Helix 2 facing the channel pore 
Hexamer_radial-hel2_t=200ns-1.gro	Final snapshot with a heptameric radial structure  of the chanel with Helix 2  facing the channel pore 
Hexamer_radial-hel2_t=200ns-2.gro	Final snapshot with a heptameric radial structure  of the chanel with Helix 2 facing the channel pore 
Hexamer_radial-hel2_t=200ns-3.gro	Final snapshot with a heptameric radial structure  of the chanel with Helix 2 facing the channel pore 
md.hexamer_compact_hel3_protonated-1.xtc	Trajectory from the simulation with the Hexamer protonated compact model with Helix 3 facing the channel pore 
md.hexamer_compact_hel3_protonated-2.xtc	Trajectory from the simulation with the Hexamer protonated compact model with Helix 3 facing the channel pore 
md.hexamer_compact_hel3_protonated-3.xtc	Trajectory from the simulation with the Hexamer protonated compact model with Helix 3 facing the channel pore 
md.hexamer_compact_hel3-1.xtc	Trajectory from the simulation with the Hexamer compact model with Helix 3 facing the channel pore 
md.hexamer_compact_hel3-2.xtc	Trajectory from the simulation with the Hexamer compact model with Helix 3 facing the channel pore 
md.hexamer_compact_hel3-3.xtc	Trajectory from the simulation with the Hexamer compact model with Helix 3 facing the channel pore 
md.hexamer_radial_hel3-1.xtc	Trajectory from the simulation with the Hexamer radial model with Helix 3 facing the channel pore 
md.hexamer_radial_hel3-2.xtc	Trajectory from the simulation with the Hexamer radial model with Helix 3 facing the channel pore 
md.hexamer_radial_hel3-3.xtc	Trajectory from the simulation with the Hexamer radial model with Helix 3 facing the channel pore 
md.Zika_EM-1_skip.xtc	Trajectory  from the simulation with the Zika monomer taken from the published EM structure  
md.Zika_EM-2_skip.xtc	Trajectory  from the simulation with the Zika monomer taken from the published EM structure  
md.Zika_EM-3_skip.xtc	Trajectory  from the simulation with the Zika monomer taken from the published EM structure  
md.Zika_EM-4_skip.xtc	Trajectory  from the simulation with the Zika monomer taken from the published EM structure  
md.Zika_EM-5_skip.xtc	Trajectory  from the simulation with the Zika monomer taken from the published EM structure  
md.Zika_Helix_str-1_skip.xtc	Trajecory  from the simulation with the Zika monomer in which the helices are in a straight conformation  
md.Zika_Helix_str-2_skip.xtc	Trajecory  from the simulation with the Zika monomer in which the helices are in a straight conformation  
md.Zika_Helix_str-3_skip.xtc	Trajecory  from the simulation with the Zika monomer in which the helices are in a straight conformation  
md.Zika_Helix_str-4_skip.xtc	Trajecory  from the simulation with the Zika monomer in which the helices are in a straight conformation  
md.Zika_Helix_str-5_skip.xtc	Trajecory  from the simulation with the Zika monomer in which the helices are in a straight conformation  
P2_Hexamer_38aa_POPC_t=0.gro	Initial snapshot with a hexameric  structure  of the chanel with Helix 1  is removed; channel consists of helices 2 and 3
P2_Hexamer_38aa_POPC_t=50ns-1.gro	Final snapshot with a hexameric  structure  of the chanel with Helix 1  is removed; channel consists of helices 2 and 3
P2_Hexamer_38aa_POPC_t=50ns-2.gro	Final snapshot with a hexameric  structure  of the chanel with Helix 1  is removed; channel consists of helices 2 and 3
P2_Hexamer_38aa_POPC_t=50ns-3.gro	Final snapshot with a hexameric  structure  of the chanel with Helix 1  is removed; channel consists of helices 2 and 3


5. METHODS
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All the methods are described in the following publication: Brown et al.; Inhibitors of the Small Membrane (M) Protein Viroporin Prevent Zika Virus Infection, 2024, eLife