The Dynamic Behavior of the P2X4 Ion Channel in the Closed Conformation

Abstract

We present the results of a detailed molecular dynamics study of the closed form of the P2X 4 receptor. The fluctuations observed in the simulations were compared with the changes that occur in the transition from the closed to the open structure. To get further insight on the opening mechanism, the actual displacements were decomposed into interchain motions and intrachain deformations. This analysis revealed that the iris-like expansion of the transmembrane helices mainly results from interchain motions that already take place in the closed conformation. However, these movements cannot reach the amplitude required for the opening of the channel because they are impeded by interactions occurring around the ATP binding pocket. This suggests that the union of ATP produces distortions in the chains that eliminate the restrictions on the interchain displacements, leading to the opening of the pore.

Exploring conformational states and helical packings in the P2X receptor transmembrane domain by molecular dynamics simulation

“…This organization is very important for channel gating. The current data support a model of gating that changes primarily in azimuth angles of the M2 helices and produces an iris-like motion of the PLHs [7,19,20] and regulates the pore geometry (Supplementary movie 1). The increase in azimuth angles has three consequences.…”

Decrypting the Information Exchange Pathways across the Spliceosome Machinery

“…The PCA has been extensively and successfully applied in many distinct applications of biological systems; however, it is wellknown that limited sampling may reduce the confidence in most representative motions identified in the sampled trajectories. 30,31 At variance with previous simulations of the SPL in which the multireplica approach was employed to validate at qualitative level the reproducibility of the results, 10,11 here PCA has been conducted on single trajectories as well as on merged trajectories (Figures S1 and S2 in the Supporting Information), generated by concatenating three or five replicas 32,33 in order to increase the sampling of this large system. Nevertheless, due to their limited sampling overlap, we have also verified that the observed essential dynamics projected on both PC1 and PC2 were independent from the manipulation of the trajectory (i.e., if this pseudotrajectory was qualitatively alike to that decrypted from the single replicas).…”

Charge Discrimination in P2X4 Receptors Occurs in Two Consecutive Stages

“…The initial structure of the closed conformation was taken from the Protein Data Bank, entry 3I5D . The protein model employed in the current calculations was built from this crystal structure, by applying the adjustments described in ref . The dimensions of the lipid bilayer were also the same as in ref .…”

“…The presentation of the crystal structure of hP2X 3 was accompanied by MD simulations, which showed that the cytoplasmic fenestrations were a plausible route for ion egress . Finally, the dynamics of the closed conformation was analyzed by decomposing its fluctuations into intra-chain deformations and inter-chain movements …”