Revealing ion exchange mechanisms in Nav1.5 channel using steered molecular dynamics simulations

Nav1.5 is one of the major isoforms of voltage-dependent sodium channels that plays significant roles in the initiation and conductance of action potentials in the heart. Abnormalities in Nav1.5 channel have been associated... [ view full abstract ]

Nav1.5 is one of the major isoforms of voltage-dependent sodium channels that plays significant roles in the initiation and conductance of action potentials in the heart. Abnormalities in Nav1.5 channel have been associated with a range of cardiac diseases. Selective permeation of sodium through the Nav1.5 channel is vital in the generation of action potentials. Nevertheless, there is very little information about the pathways and mechanisms through which the sodium ions are released from the Nav1.5 transmembrane into the cell. Molecular dynamics (MD) is a powerful approach to reveal such atomistic level details of biological systems. However, given the large size of the ion channel, it remains a critical challenge to simulate it for very long time-scale (~microseconds), such that natural permeation of sodium through the channel can be studied in detail. In order to overcome such shortcomings with the MD methods, we have employed a ‘state-of-the-art’ steered MD method, which is a non-equilibrium approach to study the most intricate chemical reactions. The availability of high-performance computers (HPCs) is very important to perform these simulations. In this work, we took the advantages of the all-powerful Blue Gene\Q supercomputer of compute Canada and performed more than eighty SMD simulations to reveal the key mechanistic insights into the ion permeation through Nav1.5. The results from this study have the potential to open up novel avenues for rationally designing small molecule drugs to target the channel. This work could be an excellent display of the importance of HPCs to drive next-generation drug discovery.