Modeling ion permeation in wild-type and mutant human α7 nachr ion channels

Abstract

Molecular dynamics simulations of wild type and two mutant (T248F and L251T) human [Formula: see text]7 nicotinic acetylcholine receptors (nAChR) have been performed. The channel transmembrane domains were modeled from the closed channel structure from torpedo ray (PDB ID 2BG9) and embedded in DPPC lipid bilayers, surrounded by physiological saline solution. An external electric field was used to obtain stable open channel structures. The adaptive biasing force (ABF) method was used to obtain potential of mean force (PMF) profiles for Na[Formula: see text] ion translocation through the wild type and mutant receptors. Based on the geometry and PMF profiles, the channel gate was found to be at one of the two hydrophobic conserved regions (V249-L251) near the lower end of the channel. The L251T mutation reduced the energetic barrier by 1.9[Formula: see text]kcal/mol, consistent with a slight increase in the channel radius in the bottleneck region. On the other hand, the T248F mutation caused a significant decrease in the channel radius (0.4 Å) and a substantial increase of 3.9[Formula: see text]kcal/mol in the energetic barrier. Ion permeation in all three structures was compared and found to be consistent with barrier height values. Using an external field in an incrementally increasing manner was found to be an effective way to obtain stable open, conducting channel structures.