Calcium interactions with Cx26 hemmichannel: Spatial association between MD simulations biding sites and variant pathogenicity
Connexinophaties are a collective of diseases related to connexin channels and hemichannels. In particular many Cx26 alterations are strongly associated to human deafness. Calcium plays an important role on this structures regulation. Here, using calcium as a probe, extensive atomistic Molecular Dyn...
Guardado en:
| Autores principales: | , , , , , |
|---|---|
| Formato: | JOUR |
| Materias: | |
| Acceso en línea: | http://hdl.handle.net/20.500.12110/paper_14769271_v77_n_p331_Albano |
| Aporte de: |
| id |
todo:paper_14769271_v77_n_p331_Albano |
|---|---|
| record_format |
dspace |
| spelling |
todo:paper_14769271_v77_n_p331_Albano2023-10-03T16:18:59Z Calcium interactions with Cx26 hemmichannel: Spatial association between MD simulations biding sites and variant pathogenicity Albano, J.M.R. Mussini, N. Toriano, R. Facelli, J.C. Ferraro, M.B. Pickholz, M. Connexin Molecular dynamics POPC Variant annotation Association reactions Binding sites Genes Lipid bilayers Molecular dynamics Amino acid interactions Atomistic molecular dynamics simulations Calcium concentration Calcium distributions Connexin Electron density profiles POPC Variant annotation Calcium calcium DFNA3 protein, human gap junction protein binding site chemistry genetics hearing impairment human lipid bilayer metabolism molecular dynamics mutation Binding Sites Calcium Connexins Deafness Humans Lipid Bilayers Molecular Dynamics Simulation Mutation Connexinophaties are a collective of diseases related to connexin channels and hemichannels. In particular many Cx26 alterations are strongly associated to human deafness. Calcium plays an important role on this structures regulation. Here, using calcium as a probe, extensive atomistic Molecular Dynamics simulations were performed on the Cx26 hemichannel embedded in a lipid bilayer. Exploring different initial conditions and calcium concentration, simulation reached ∼4 μs. Several analysis were carried out in order to reveal the calcium distribution and localization, such as electron density profiles, density maps and distance time evolution, which is directly associated to the interaction energy. Specific amino acid interactions with calcium and their stability were capture within this context. Few of these sites such as, GLU42, GLU47, GLY45 and ASP50, were already suggested in the literature. Besides, we identified novel calcium biding sites: ASP2, ASP117, ASP159, GLU114, GLU119, GLU120 and VAL226. To the best of our knowledge, this is the first time that these sites are reported within this context. Furthermore, since various pathologies involving the Cx26 hemichannel are associated with pathogenic variants in the corresponding CJB2 gene, using ClinVar, we were able to spatially associate the 3D positions of the identified calcium binding sites within the framework of this work with reported pathogenic variants in the CJB2 gene. This study presents a first step on finding associations between molecular features and pathological variants of the Cx26 hemichannel. © 2018 Elsevier Ltd JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_14769271_v77_n_p331_Albano |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Connexin Molecular dynamics POPC Variant annotation Association reactions Binding sites Genes Lipid bilayers Molecular dynamics Amino acid interactions Atomistic molecular dynamics simulations Calcium concentration Calcium distributions Connexin Electron density profiles POPC Variant annotation Calcium calcium DFNA3 protein, human gap junction protein binding site chemistry genetics hearing impairment human lipid bilayer metabolism molecular dynamics mutation Binding Sites Calcium Connexins Deafness Humans Lipid Bilayers Molecular Dynamics Simulation Mutation |
| spellingShingle |
Connexin Molecular dynamics POPC Variant annotation Association reactions Binding sites Genes Lipid bilayers Molecular dynamics Amino acid interactions Atomistic molecular dynamics simulations Calcium concentration Calcium distributions Connexin Electron density profiles POPC Variant annotation Calcium calcium DFNA3 protein, human gap junction protein binding site chemistry genetics hearing impairment human lipid bilayer metabolism molecular dynamics mutation Binding Sites Calcium Connexins Deafness Humans Lipid Bilayers Molecular Dynamics Simulation Mutation Albano, J.M.R. Mussini, N. Toriano, R. Facelli, J.C. Ferraro, M.B. Pickholz, M. Calcium interactions with Cx26 hemmichannel: Spatial association between MD simulations biding sites and variant pathogenicity |
| topic_facet |
Connexin Molecular dynamics POPC Variant annotation Association reactions Binding sites Genes Lipid bilayers Molecular dynamics Amino acid interactions Atomistic molecular dynamics simulations Calcium concentration Calcium distributions Connexin Electron density profiles POPC Variant annotation Calcium calcium DFNA3 protein, human gap junction protein binding site chemistry genetics hearing impairment human lipid bilayer metabolism molecular dynamics mutation Binding Sites Calcium Connexins Deafness Humans Lipid Bilayers Molecular Dynamics Simulation Mutation |
| description |
Connexinophaties are a collective of diseases related to connexin channels and hemichannels. In particular many Cx26 alterations are strongly associated to human deafness. Calcium plays an important role on this structures regulation. Here, using calcium as a probe, extensive atomistic Molecular Dynamics simulations were performed on the Cx26 hemichannel embedded in a lipid bilayer. Exploring different initial conditions and calcium concentration, simulation reached ∼4 μs. Several analysis were carried out in order to reveal the calcium distribution and localization, such as electron density profiles, density maps and distance time evolution, which is directly associated to the interaction energy. Specific amino acid interactions with calcium and their stability were capture within this context. Few of these sites such as, GLU42, GLU47, GLY45 and ASP50, were already suggested in the literature. Besides, we identified novel calcium biding sites: ASP2, ASP117, ASP159, GLU114, GLU119, GLU120 and VAL226. To the best of our knowledge, this is the first time that these sites are reported within this context. Furthermore, since various pathologies involving the Cx26 hemichannel are associated with pathogenic variants in the corresponding CJB2 gene, using ClinVar, we were able to spatially associate the 3D positions of the identified calcium binding sites within the framework of this work with reported pathogenic variants in the CJB2 gene. This study presents a first step on finding associations between molecular features and pathological variants of the Cx26 hemichannel. © 2018 Elsevier Ltd |
| format |
JOUR |
| author |
Albano, J.M.R. Mussini, N. Toriano, R. Facelli, J.C. Ferraro, M.B. Pickholz, M. |
| author_facet |
Albano, J.M.R. Mussini, N. Toriano, R. Facelli, J.C. Ferraro, M.B. Pickholz, M. |
| author_sort |
Albano, J.M.R. |
| title |
Calcium interactions with Cx26 hemmichannel: Spatial association between MD simulations biding sites and variant pathogenicity |
| title_short |
Calcium interactions with Cx26 hemmichannel: Spatial association between MD simulations biding sites and variant pathogenicity |
| title_full |
Calcium interactions with Cx26 hemmichannel: Spatial association between MD simulations biding sites and variant pathogenicity |
| title_fullStr |
Calcium interactions with Cx26 hemmichannel: Spatial association between MD simulations biding sites and variant pathogenicity |
| title_full_unstemmed |
Calcium interactions with Cx26 hemmichannel: Spatial association between MD simulations biding sites and variant pathogenicity |
| title_sort |
calcium interactions with cx26 hemmichannel: spatial association between md simulations biding sites and variant pathogenicity |
| url |
http://hdl.handle.net/20.500.12110/paper_14769271_v77_n_p331_Albano |
| work_keys_str_mv |
AT albanojmr calciuminteractionswithcx26hemmichannelspatialassociationbetweenmdsimulationsbidingsitesandvariantpathogenicity AT mussinin calciuminteractionswithcx26hemmichannelspatialassociationbetweenmdsimulationsbidingsitesandvariantpathogenicity AT torianor calciuminteractionswithcx26hemmichannelspatialassociationbetweenmdsimulationsbidingsitesandvariantpathogenicity AT facellijc calciuminteractionswithcx26hemmichannelspatialassociationbetweenmdsimulationsbidingsitesandvariantpathogenicity AT ferraromb calciuminteractionswithcx26hemmichannelspatialassociationbetweenmdsimulationsbidingsitesandvariantpathogenicity AT pickholzm calciuminteractionswithcx26hemmichannelspatialassociationbetweenmdsimulationsbidingsitesandvariantpathogenicity |
| _version_ |
1807323963089485824 |