Homology Modeling and Molecular Dynamics Simulations of Transmembrane Domain Structure of Human Neuronal Nicotinic Acetylcholine Receptor

Abstract

A three-dimensional model of the transmembrane domain of a neuronal-type nicotinic acetylcholine receptor (nAChR), (alpha4)2(beta2)3, was constructed from a homology structure of the muscle-type nAChR recently determined by cryo-electron microscopy. The neuronal channel model was embedded in a fully hydrated DMPC lipid bilayer, and molecular-dynamics simulations were performed for 5 ns. A comparative analysis of the neuronal- versus muscle-type nAChR models revealed many conserved pore-lining residues, but an important difference was found near the periplasmic mouth of the pore. A flickering salt-bridge of alpha4-E266 with its adjacent beta2-K260 was observed in the neuronal-type channel during the course of the molecular-dynamics simulations. The narrowest region, with a pore radius of approximately 2 A formed by the salt-bridges, does not seem to be the restriction site for a continuous water passage. Instead, two hydrophobic rings, formed by alpha4-V259, alpha4-L263, and the homologous residues in the beta2-subunits, act as the gates for water flow, even though the region has a slightly larger pore radius. The model offers new insight into the water transport across the (alpha4)2(beta2)3 nAChR channel, and may lead to a better understanding of the structures, dynamics, and functions of this family of ion channels.

Targeted molecular dynamics study of C-loop closure and channel gating in nicotinic receptors

“…Henchman et al studied the dynamics of the ligand-binding domain of the human a7 nicotinic receptor, and observed asymmetrical motions in the presence of different ligands [20]. MD simulations of the transmembrane domain investigated the dynamics of the M2 helices [21][22][23], the importance of the hydrophobic gates [24,25], and the lipid-M4 interactions [26]. More recently, a simulation on the human a7 nAChR with both the ligand-binding and transmembrane domains revealed that the protein undergoes a twist-to-close motion that correlates movements of the Cloop with the rotation and inward movement of two nonadjacent subunits [27].…”

Significances of protein structure and dynamics in anesthetic action

“…The salt bridges could last for several nanoseconds, and sometimes two salt bridges could be formed simultaneously. Detailed analyses [10] indicate that the extracellular mouth of the pore has the narrowest radius, but this physical restriction does not occlude the water passage in this region of the pore. The energy barrier restricting the water passage occurs almost two helix turns into the channel at a hydrophobic girdle formed by a4-Val 259 and a4-Leu 263 and the analogous h2-Val 253 and h2-Leu 257 , which may act as a hydrophobic gate to ion permeations.…”

“…The details of the studies discussed below have been published elsewhere [8][9][10][11][12][13][14][15]. Here we give an overview of the major conclusions from these studies.…”

“…We also carried out homology modeling and large-scale molecular dynamics simulations of the TM domains of neuronal (a4) 2 (h2) 3 nAChR [10] using the 4-Å cryo-EM structure [18] of the muscle-type nAChR as a template. The neuronal (a4) 2 (h2) 3 nAChR model was embedded in a fully hydrated DMPC lipid bilayer, and all-atom simulations were performed for 5 ns.…”

Mechanism of the plant cytochrome P450 for herbicide resistance: a modelling study

“…In a typical RMSF pattern, a low RMSF value indicates the well-structured regions while the high values indicate the loosely structured loop regions or domains terminal 45 . As shown in Figure 3, the major backbone fluctuation was seen to occur in the loop regions, whereas regions with low RMSF correspond exclusively to the rigid beta-alpha-beta fold.…”