Data of the molecular dynamics simulations of mutations in the human connexin46 docking interface

Abstract

The structure of hCx26 derived from the X-ray analysis was used to generate a homology model for hCx46. Interacting connexin molecules were used as starting model for the molecular dynamics (MD) simulation using NAMD and allowed us to predict the dynamic behavior of hCx46wt and the cataract related mutant hCx46N188T as well as two artificial mutants hCx46N188Q and hCx46N188D. Within the 50 ns simulation time the docked complex composed of the mutants dissociate while hCx46wt remains stable. The data indicates that one hCx46 molecule forms 5–7 hydrogen bonds (HBs) with the counterpart connexin of the opposing connexon. These HBs appear essential for a stable docking of the connexons as shown by the simulation of an entire gap junction channel and were lost for all the tested mutants.The data described here are related to the research article entitled “The cataract related mutation N188T in human connexin46 (hCx46) revealed a critical role for residue N188 in the docking process of gap junction channels” (Schadzek et al., 2015) [1].

Analysis of the dominant mutation N188T of human connexin46 (hCx46) using concatenation and molecular dynamics simulation

“…Previously, we analyzed the stability of the interaction in a structural model of docked hCx46 Cx, derived from the crystal structure of hCx26, in silico [12]. We could show that the hCx46N188T mutation destabilized the Cx interaction, which indicated that the docking of mutated connexons of adjacent cells might be affected [31]. In the present report, we extended our study by classical MD simulations, including hexamers composed of either hCx46wt, hCx46N188T, or alternating hCx46wt and hCx46N188T protomers.…”

Molecular dynamics simulations for genetic interpretation in protein coding regions: where we are, where to go and when

“…The promising results obtained in works where classical atomistic MD simulations with explicit water were performed [47,54,110,116,119] reinforce the idea that using MD-based methods under realistic conditions allows to accurately model and reveal the complexity of the structural changes associated to point mutations in proteins. In previous work, we followed this approach to explore the complete t-HumanV of the low-density lipoprotein receptor (LDL-r) LA5 domain by performing all-atom rMD simulations in explicit solvent.…”

“…Nevertheless, such efforts have not led to significant increases in MEPTs' accuracies so far [108]. Looking for new approaches to enhance MEPTs' reliabilities, researchers have begun to exploit the availability of 3D protein structures to include dynamic aspects of proteins in the prediction of mutation effects [40,47,54,[109][110][111][112][113][114][115][116][117][118][119][120]. As protein function is defined by both structure and dynamics [121][122][123], dynamic patterns have begun to be recognized as descriptive of proteins [124,125].…”

“…Given the artifactual nature of the starting model, the pertinence of this approach may be arguable. Nevertheless, a number of rMD-based approaches have been used to study mutation effects on phenotypes in the last few years [47,54,110,116,117,119]. Many of these works showed quite good correlations between their predictions and experimental data and, at the same time, allowed to extract meaningful insights underlying the mechanisms through which mutations impair protein function.…”

Concatenation of Human Connexin26 (hCx26) and Human Connexin46 (hCx46) for the Analysis of Heteromeric Gap Junction Hemichannels and Heterotypic Gap Junction Channels

“…The analysis of hCx26, for which a crystal structure was generated, revealed that each asparagine residue at position 176 (N176) in a hemichannel formed three hydrogen bonds with a lysine residue at position 168 (K168), a threonine residue at position 177 (T177), and an aspartic acid residue at position 179 (D179) in the E2 domain of the counterpart hCx26 in the hemichannel of the adjacent cell [ 6 , 7 , 8 , 9 , 11 , 14 , 15 , 16 , 17 , 18 ]. For hCx32 and hCx46, homologous N residues to N176 were described [ 12 , 13 , 19 , 20 ]. For hCx32, the central N residue was N175, which interacted with K167, T176, and D178.…”