Computational methods play key roles to study the mechanism of ion channel with a charged molecular. Connexin ion channel can form gap junction which is located in between two adjacent cells to help permeation of ions or small molecules. The diseases can be caused by mutation of connexin include heart disease, nervous system disease, skin disease and cancers. In order to understand the permeation of a negatively charged second messenger cyclic AMP (cAMP) and a positively charged dye molecule ethidium through connexin26, we first conducted molecular dynamics (MD) simulation of Cx26 hemichannel under the positive and negative voltage. Under those two voltage environments, the location of the binding sites and energy barrier of the ligands inside connexin channel were obtained. Next, we sampled the permeation of a single charged molecule and potassium ion in Cx26 with zero voltage. With zero voltage simulation, it could provide the intrinsic free energy profile for a charged molecule permeating through the Cx26 ion channel. Markovian milestone sampling method was used to obtain the free energy and kinetics of the permeation process, and compared with the results from voltage simulation.

Small molecule permeation through a wide-pore channel via applied voltage and Markovian milestoning

ACS Fall 2021

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