Abstract
This study explores the ion selectivity and conduction mechanisms of the hNa(V)1.5 sodium channel using classical molecular dynamics simulations under an externally applied electric field. Our findings reveal distinct conduction mechanisms for Na(+) and K(+), primarily driven by differences in their hydration states when they diffuse close to the channel's selective filter (DEKA) and extracellular ring (EEDD). The Na(+) ions undergo partial dehydration in the EEDD region, followed by a rehydration step in the DEKA ring, resulting in longer retention times and a deeper free energy minimum compared to K(+). Conversely, the K(+) ions exhibit a continuous dehydration process, facilitating a smoother passage through these key regions. These results indicate that ion selectivity and conductance are primarily governed by solvation dynamics, which, in turn, depend on the interactions with key charged residues within the channel. Additionally, we show that the delicate energetic balance between the interactions of the ions with the protein residues and with their solvation shells during the dehydration and rehydration processes is not properly captured by the force field. As a consequence, the selectivity of the channel is not well described, indicating that more accurate computational models must be applied to simulate ion conduction through eukaryotic Na(V) channels.