| Title |
Modeling the human Nav1.5 sodium channel: structural and mechanistic insights of ion permeation and drug blockade
|
|---|---|
| Published in |
Drug Design, Development and Therapy, August 2017
|
| DOI | 10.2147/dddt.s133944 |
| Pubmed ID | |
| Authors |
Marawan Ahmed, Horia Jalily Hasani, Aravindhan Ganesan, Michael Houghton, Khaled Barakat |
| 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. |
X Demographics
The data shown below were collected from the profile of 1 X user who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 1 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Scientists | 1 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 70 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 70 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Ph. D. Student | 17 | 24% |
| Student > Bachelor | 13 | 19% |
| Student > Doctoral Student | 6 | 9% |
| Professor | 4 | 6% |
| Researcher | 4 | 6% |
| Other | 12 | 17% |
| Unknown | 14 | 20% |
| Readers by discipline | Count | As % |
|---|---|---|
| Biochemistry, Genetics and Molecular Biology | 16 | 23% |
| Chemistry | 9 | 13% |
| Agricultural and Biological Sciences | 7 | 10% |
| Pharmacology, Toxicology and Pharmaceutical Science | 6 | 9% |
| Medicine and Dentistry | 6 | 9% |
| Other | 10 | 14% |
| Unknown | 16 | 23% |
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 05 May 2020.
All research outputs
#20,125,075
of 25,604,262 outputs
Outputs from Drug Design, Development and Therapy
#1,318
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Outputs of similar age
#238,942
of 328,070 outputs
Outputs of similar age from Drug Design, Development and Therapy
#36
of 47 outputs
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