Abstract
BackgroundMutation-induced variations in the functional architecture of the NaV1.7 channel protein are causally related to a broad spectrum of human pain disorders. Predicting in silico the phenotype of NaV1.7 variant is of major clinical importance; it can aid in reducing costs of in vitro pathophysiological characterization of NaV1.7 variants, as well as, in the design of drug agents for counteracting pain-disease symptoms.ResultsIn this work, we utilize spatial complexity of hydropathic effects toward predicting which NaV1.7 variants cause pain (and which are neutral) based on the location of corresponding mutation sites within the NaV1.7 structure. For that, we analyze topological and scaling hydropathic characteristics of the atomic environment around NaV1.7’s pore and probe their spatial correlation with mutation sites. We show that pain-related mutation sites occupy structural locations in proximity to a hydrophobic patch lining the pore while clustering at a critical hydropathic-interactions distance from the selectivity filter (SF). Taken together, these observations can differentiate pain-related NaV1.7 variants from neutral ones, i.e., NaV1.7 variants not causing pain disease, with 80.5% sensitivity and 93.7% specificity [area under the receiver operating characteristics curve = 0.872].ConclusionsOur findings suggest that maintaining hydrophobic NaV1.7 interior intact, as well as, a finely-tuned (dictated by hydropathic interactions) distance from the SF might be necessary molecular conditions for physiological NaV1.7 functioning. The main advantage for using the presented predictive scheme is its negligible computational cost, as well as, hydropathicity-based biophysical rationalization.
Highlights
Voltage-gated sodium channels (NaVChs) are pore-forming proteins embedded in cell membranes
The atomic environment around the pore can be partitioned into three consecutive atom-packing domains spanning the channel from the inside to the outside (Fig. 1b, c)
The outermost domain corresponds to the asymptote domain consisting mostly of structural elements drawn from the S1–S4 voltage-sensing helices
Summary
Voltage-gated sodium channels (NaVChs) are pore-forming proteins embedded in cell membranes. They are members of the ion channels superfamily and their main physiological role is to control transport of sodium ions into the cell. Missense mutations in the SCN9A gene can destabilize the NaV1.7’s functional architecture disrupting physiological sodium-ions current and, deregulate flow of sodium ions through the pore. A proof of concept for the GOF-pain correlation hypothesis came from identification of missense SCN9A-gene mutations inducing a loss-of-function (LOF) effect, i.e., decreasing net sodium-ions current, that is causally related to clinical symptoms of loss of pain sensation [43,44,45]. Mutation-induced variations in the functional architecture of the NaV1.7 channel protein are causally related to a broad spectrum of human pain disorders. Predicting in silico the phenotype of NaV1.7 variant is of major clinical importance; it can aid in reducing costs of in vitro pathophysiological characterization of NaV1.7 variants, as well as, in the design of drug agents for counteracting pain-disease symptoms
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