Modeling the human Na_v1.5 sodium channel: structural and mechanistic insights of ion permeation and drug blockade

Abstract

Abnormalities in the human Nav1.5 (hNav1.5) voltage-gated sodium ion channel (VGSC) are associated with a wide range of cardiac problems and diseases in humans. Current structural models of hNav1.5 are still far from complete and, consequently, their ability to study atomistic interactions of this channel is very limited. Here, we report a comprehensive atomistic model of the hNav1.5 ion channel, constructed using homology modeling technique and refined through long molecular dynamics simulations (680 ns) in the lipid membrane bilayer. Our model was comprehensively validated by using reported mutagenesis data, comparisons with previous models, and binding to a panel of known hNav1.5 blockers. The relatively long classical MD simulation was sufficient to observe a natural sodium permeation event across the channel’s selectivity filters to reach the channel’s central cavity, together with the identification of a unique role of the lysine residue. Electrostatic potential calculations revealed the existence of two potential binding sites for the sodium ion at the outer selectivity filters. To obtain further mechanistic insight into the permeation event from the central cavity to the intracellular region of the channel, we further employed “state-of-the-art” steered molecular dynamics (SMD) simulations. Our SMD simulations revealed two different pathways through which a sodium ion can be expelled from the channel. Further, the SMD simulations identified the key residues that are likely to control these processes. Finally, we discuss the potential binding modes of a panel of known hNav1.5 blockers to our structural model of hNav1.5. We believe that the data presented here will enhance our understanding of the structure–property relationships of the hNav1.5 ion channel and the underlying molecular mechanisms in sodium ion permeation and drug interactions. The results presented here could be useful for designing safer drugs that do not block the hNav1.5 channel.

Challenges and advances in atomistic simulations of potassium and sodium ion channel gating and permeation

“…Several recent MD studies used eukaryotic Na V homology models (Mahdavi & Kuyucak, ; Ahmed et al . ), hybrid models with a grafted SF eukaryotic Na V channel SF onto bacterial structures (Li et al . ; Flood et al .…”

“…Their SFs display asymmetries with aspartic acid, glutamic acid, lysine and alanine (DEKA) from different channel domains forming Na + binding site Site HFS compared to the EEEE ring in prokaryotic channels. Several recent MD studies used eukaryotic Na V homology models (Mahdavi & Kuyucak, 2015;Ahmed et al 2017), hybrid models with a grafted SF eukaryotic Na V channel SF onto bacterial structures (Li et al 2017b;Flood et al 2018) as well as new Na V PaS structure . These studies identified a unique asymmetric Na + permeation pathway involving coordination with Asp and Glu residues in the DEKA ring as well as in the outer SF.…”

Guanidinium Toxins and Their Interactions with Voltage-Gated Sodium Ion Channels

“…The first pioneering MD simulation with the peptide neurotoxin I (SH1) from the sea anemone Stichodactyla helianthus was conducted in 1991 [ 163 ]. A later important step in MD application to Na V channel research was the generation of homology model simulations of the Na V channel recognition properties towards the tarantula peptide toxin psalmotoxin-1 [ 164 ], which can bind to a particular isoform (ASIC1) of the Acid Sensing Ion Channel. Although ASICs are proton-gated Na + channels and open when H + binds, unlike the Na V channels involved in recognition of guanidinium toxins, the general MD modelling approach should be applicable for these non-peptidic toxins.…”

L-Type Calcium Channels: Structure and Functions

“…Nevertheless, sophisticated methods and high-performance computing would be needed for modeling the multi-domain architecture of the human CaVs. Building these models can be helpful in understanding the structure-function-dynamic properties, the Ca 2+ influx mechanisms and effects of small molecules on these channels [48,49].…”