A new gating site in human aquaporin-4: Insights from molecular dynamics simulations

Abstract

Aquaporin-4 (AQP4) is the predominant water channel in different organs and tissues. An alteration of its physiological functioning is responsible for several disorders of water regulation and, thus, is considered an attractive target with a promising therapeutic and diagnostic potential. Molecular dynamics (MD) simulations performed on the AQP4 tetramer embedded in a bilayer of lipid molecules allowed us to analyze the role of spontaneous fluctuations occurring inside the pore. Following the approach by Hashido et al. [Hashido M, Kidera A, Ikeguchi M (2007) Biophys J 93: 373-385], our analysis on 200ns trajectory discloses three domains inside the pore as key elements for water permeation. Herein, we describe the gating mechanism associated with the well-known selectivity filter on the extracellular side of the pore and the crucial regulation ensured by the NPA motifs (asparagine, proline, alanine). Notably, on the cytoplasmic side, we find a putative gate formed by two residues, namely, a cysteine belonging to the loop D (C178) and a histidine from loop B (H95). We observed that the spontaneous reorientation of the imidazole ring of H95 acts as a molecular switch enabling H-bond interaction with C178. The occurrence of such local interaction seems to be responsible for the narrowing of the pore and thus of a remarkable decrease in water flux rate. Our results are in agreement with recent experimental observations and may represent a promising starting point to pave the way for the discovery of chemical modulators of AQP4 water permeability.

Erythritol predicted to inhibit permeation of water and solutes through the conducting pore of P. falciparum aquaporin

“…3) in the same way as for PfAQP, predicting an Arrhenius activation barrier of 3.4±0.6 kcal/mol for water transport that is in agreement with the experimental value of 3 kcal/mol[23] and consistent with recent in silico studies of AQP4. [31, 32] The agreement between this in silico prediction and the in vitro studies of AQPZ should strongly indicate the validity of the approach of this work.…”

“…S1), similar to Refs. [31, 32]. The PfAQP-membrane system with glycerols was fully described in Ref.…”

Rat Aquaporin-5 Is pH-Gated Induced by Phosphorylation and Is Implicated in Oxidative Stress

“…The trigger for this gating mechanism has not been described; in addition, this in silico approach has not been so far experimentally validated. A similar gating mechanism for human AQP4 was recently described [34], where two putative gate regions formed by two residues on the cytoplasmic side (His95 and Cys178) and the other two on the SF region (Arg216 and His201) modulate opening and closure of the AQP4 pore along four possible conformational states. The relative stability of the two resulting states, open and closed, may depend on small changes in the microenvironment, such as variations of pH.…”

Challenging AQP4 druggability for NMO-IgG antibody binding using molecular dynamics and molecular interaction fields

“…In a previous study [26], we found that two different gating mechanisms can exist inside the water pore of WT. One is associated with the well-known selectivity filter (SF) on the extracellular side (residues H201 and R216); the other to the spontaneous reorientation of the imidazole ring of a histidine from loop B (H95) enabling an H-bond interaction with a cysteine belonging to the loop D (C178) at the cytoplasmic end (CE).…”

“…The longer simulation time allowed us to identify the reorientation of the side chain of T62 as a key element for epitope recognition and thus for NMO-IgG binding. In recent years molecular dynamics (MD) simulations proved effective to obtain important structural and mechanistic insights into the water transport of aquaporins [26][27][28][29][30][31][32][33]. Here, we employ the same technique to obtain some insight on NMO-IgG epitope reorganization.…”