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 Ca_v2.2 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 Ca_v2.2 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 Ca_v2.2 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 Ca_v2.2 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 Ca_v2.2 that may help in better therapeutic intervention to chronic and neuropathic pain management.

慢性神经性疼痛是人口中最复杂，最具挑战性的临床问题，在全球范围内造成了巨大的身体和经济负担。Ca ²⁺渗透通道在功能上协调了疼痛信号的处理。其中，N型电压门控钙通道（VGCC）在疼痛信号转导中起着重要作用，并作为突触传递阻滞和神经性疼痛减轻的主要靶标。在这里，我们提供详细的计算机分析，以了解Ca ²⁺离子通过Ca _v时的潜在构象变化2.2与通过基于肽的模拟的烷基苯基醚类似物MVIIA的结合诱导的微妙的变化差异相关。有趣的是，在Ca _v 2.2的近端羧基末端观察到明显的构象变化，该变化在Ca ⁺²离子渗透性下达到了垂直方向。此外，在通道隧道的体系结构中观察到了显着的变化。这些发现表明，与Ca _v 2.2结合的抑制剂与Ca ²⁺结合相比，可通过调节选择性区域的亲水性模式而引起孔径的进一步缩小。选择性过滤器的隧道体积显着减少，而Ca ⁺²的激活门处的隧道体积增加束缚Ca _v 2.2表明离子键调节了孔衬S6螺旋的向外张开，从而打开了电压门。总体而言，目前的研究描绘的钙方面动态构象合奏⁺²中的钙离子和MVIIA相关的结构性影响_v 2.2，可能更好的治疗干预，以慢性和神经性疼痛的管理帮助。