Calcium interactions with Cx26 hemmichannel: Spatial association between MD simulations biding sites and variant pathogenicity

Abstract

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.

Differential Stability of Aurein 1.2 Pores in Model Membranes of Two Probiotic Strains

“…Comparing the distribution of the peptides in each bilayer, inside the 331M bilayer, it is more uniform and denser compared to the 113M case where more peptides are found at the interphase. In contrast to what it is observed in well-organized lipid membranes, the density of water is not negligible in the hydrophobic core regions as it was already described in other simulation studies of pore-like structures . The MDPs of all the systems considered are presented in the Supporting Information (Figures S2–S6).…”

“…In contrast to what it is observed in wellorganized lipid membranes, the density of water is not negligible in the hydrophobic core regions as it was already described in other simulation studies of pore-like structures. 66 The MDPs of all the systems considered are presented in the Supporting Information (Figures S2−S6).…”

Investigating dual Ca2+ modulation of the ryanodine receptor 1 by molecular dynamics simulation

“…The rationale of using very high Ca 2+ concentrations (0.15 M, well above the physiological range of μM ~ mM) is to enable detection of weak Ca 2+ binding regions and effects within limited MD simulation times. This strategy has been extensively used in the literature, 49‐52 although one must be cautious in extrapolating the simulation findings to in vivo Ca 2+ binding under physiological conditions.…”

Study of the Lamellar and Micellar Phases of Pluronic F127: A Molecular Dynamics Approach

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