title: Near-microsecond human aquaporin 4 gating dynamics in static and alternating external electric fields: Non-equilibrium molecular dynamics.
abstract: An extensive suite of non-equilibrium molecular-dynamics simulation has been performed for ∼0.85-0.9 μs of human aquaporin 4 in the absence and presence of externally applied static and alternating electric fields applied along the channels (in both axial directions in the static case, taken as the laboratory z-axis). These external fields were of 0.0065 V/Å (r.m.s.) intensity (of the same order as physiological electrical potentials); alternating fields ranged in frequency from 2.45 to 500 GHz. In-pore gating dynamics was studied, particularly of the relative propensities for "open" and "closed" states of the conserved arginines in the arginine/aromatic area (itself governed in no small part by external-field response of the dipolar alignment of the histidine-201 residue in the selectivity filter). In such a manner, the intimate connection of field-response governing "two-state" histidine states was established statistically and mechanistically. Given the appreciable size of the energy barriers for histidine-201 alignment, we have also performed non-equilibrium metadynamics/local-elevation of static fields applied along both directions to construct the free-energy landscape thereof in terms of external-field direction, elucidating the importance of field direction on energetics. We conclude from direct measurement of deterministic molecular dynamics in conjunction with applied-field metadynamics that the intrinsic electric field within the channel points along the +z-axis, such that externally applied static fields in this direction serve to "open" the channel in the selectivity-filter and the asparagine-proline-alanine region.
authors: School of Chemical and Bioprocess Engineering, University College Dublin, Belfield, Dublin 4, Ireland.
authors: Niall J
authors: NJ
authors: English
authors: Computational Biology Laboratory, Life Sciences Foundation, Santiago, Chile.
authors: José-A
authors: JA
authors: Garate
mesh_terms: D051401:Aquaporin 4 / Q000235:genetics / Q000378:metabolism*; D001120:Arginine / Q000378:metabolism; D055590:Electromagnetic Phenomena; D006639:Histidine / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D014867:Water / Q000737:chemistry
chemical_list: C496030:AQP4 protein, human; D051401:Aquaporin 4; D014867:Water; D006639:Histidine; D001120:Arginine