Chronic neuropathic pain is the most complex and challenging clinical problem of a population that sets a major physical and economic burden at the global level. Ca2+-permeable channels functionally orchestrate the processing of pain signals. Among them, N-type voltage-gated calcium channels (VGCC) hold prominent contribution in the pain signal transduction and serve as prime targets for synaptic transmission block and attenuation of neuropathic pain. Here, we present detailed in silico analysis to comprehend the underlying conformational changes upon Ca2+ ion passage through Cav2.2 to differentially correlate subtle transitions induced via binding of a conopeptide-mimetic alkylphenyl ether-based analogue MVIIA. Interestingly, pronounced conformational changes were witnessed at the proximal carboxyl-terminus of Cav2.2 that attained an upright orientation upon Ca+2 ion permeability. Moreover, remarkable changes were observed in the architecture of channel tunnel. These findings illustrate that inhibitor binding to Cav2.2 may induce more narrowing in the pore size as compared to Ca2+ binding through modulating the hydrophilicity pattern at the selectivity region. A significant reduction in the tunnel volume at the selectivity filter and its enhancement at the activation gate of Ca+2-bound Cav2.2 suggests that ion binding modulates the outward splaying of pore-lining S6 helices to open the voltage gate. Overall, current study delineates dynamic conformational ensembles in terms of Ca+2 ion and MVIIA-associated structural implications in the Cav2.2 that may help in better therapeutic intervention to chronic and neuropathic pain management.
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