Human aquaporin 4 gating dynamics in dc and ac electric fields: A molecular dynamics study

Gárate, José-Antonio; English, Niall J.; MacElroy, J. M. D.

doi:10.1063/1.3529428

Cited by 54 publications

(103 citation statements)

References 57 publications

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“…To note that the figure confirms how this holds true for both the protein and the water phases, since even water molecules near charged residues act very differently from the bulk water, and they establish peculiar hydrogen bonds networks with the different residues [17,40,42].…”

Section: Resultssupporting

confidence: 78%

Evaluation of Protein Electrostatic Potential from Molecular Dynamics Simulations in the Presence of Exogenous Electric Fields: The Case Study of Myoglobin

Marracino

Casciola

Liberti

et al. 2014

Computational Electrostatics for Biological Applications

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When studying proteins in solution it is apparent that electrostatic interactions play a role in folding, conformational stability, and other chemicalphysical properties. Electrostatics considers the evaluation of the static electrical field that is formed between charged species once a rearrangement of their charge distributions has occurred due to the influence of each other and their local environment. A powerful tool used to follow the many interactions among the polar and/or charged residues is computer simulations, which can provide atomic-scale information on energetic and dynamic contributions of the bio-molecular structure. Here we use molecular dynamics (MD) simulations to map on a three-dimensional space the electrostatic interactions within the protein itself and of the protein with its aqueous environment. The method has been first tested on a simulation domain of water molecules and then applied to the myoglobin-water system. The presence of intense electric fields has also been considered and some representative results are discussed. IntroductionThe electrostatic interactions between charged atoms in natural proteins play a central role in specifying protein topology, modulating stability of the molecule, and allowing for the important catalytic properties of enzymes. Such kind of interactions are at the basis of molecular characterization; when studying biomolecules it is becoming increasingly evident that electrostatic interactions play a role in folding, conformational stability, enzyme activity, and binding energies as well as in

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Section: Resultssupporting

confidence: 78%

Evaluation of Protein Electrostatic Potential from Molecular Dynamics Simulations in the Presence of Exogenous Electric Fields: The Case Study of Myoglobin

Marracino

Casciola

Liberti

et al. 2014

Computational Electrostatics for Biological Applications

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“…When we compared four monomers (or four subunits) in each hTRPV1, the RMSF of each monomer was different, as shown in Figure 8b. These results suggest that TRPV1 works with concerted movements (not in a synchronous way), akin to some other proteins, including aquaporins 49–51 and FocA. 52 The following discussion elaborates in detail on these findings.…”

Section: Discussionmentioning

confidence: 89%

Structural Insight into Tetrameric hTRPV1 from Homology Modeling, Molecular Docking, Molecular Dynamics Simulation, Virtual Screening, and Bioassay Validations

Feng¹,

Pearce

Xu³

et al. 2015

J. Chem. Inf. Model.

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The transient receptor potential vanilloid type 1 (TRPV1) is a heat-activated cation channel protein, which contributes to inflammation, acute and persistent pain. Antagonists of human TRPV1 (hTRPV1) represent a novel therapeutic approach for the treatment of pain. Developing various antagonists of hTRPV1, however, has been hindered by the unavailability of a 3D structure of hTRPV1. Recently, the 3D structures of rat TRPV1 (rTRPV1) in the presence and absence of ligand have been reported as determined by cryo-EM. rTRPV1 shares 85.7% sequence identity with hTRPV1. In the present work, we constructed and reported the 3D homology tetramer model of hTRPV1 based on the cryo-EM structures of rTRPV1. Molecular dynamics (MD) simulations, energy minimizations, and prescreen were applied to select and validate the best model of hTRPV1. The predicted binding pocket of hTRPV1 consists of two adjacent monomers subunits, which were congruent with the experimental rTRPV1 data and the cyro-EM structures of rTRPV1. The detailed interactions between hTRPV1 and its antagonists or agonists were characterized by molecular docking, which helped us to identify the important residues. Conformational changes of hTRPV1 upon antagonist/agonist binding were also explored by MD simulation. The different movements of compounds led to the different conformational changes of monomers in hTRPV1, indicating that TRPV1 works in a concerted way, resembling some other channel proteins such as aquaporins. We observed that the selective filter was open when hTRPV1 bound with an agonist during MD simulation. For the lower gate of hTRPV1, we observed large similarities between hTRPV1 bound with antagonist and with agonist. A five-point pharmacophore model based on several antagonists was established, and the structural model was used to screen in silico for new antagonists for hTRPV1. By using the 3D TRPV1 structural model above, the pilot in silico screening has begun to yield promising hits with activity as hTRPV1 antagonists, several of which showed substantial potency.

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“…An examination of the published MD simulation results obtained for representative aquaporins from both sub-families, including AqpZ [28,31,32] and GlpF [28,31-33] from E.coli , and mammalian Aqp1 [29,31,32] and Aqp4 [31,34], revealed significant discrepancies on the values obtained for the osmotic and diffusive water permeability and the p f / p d ratio for the same aquaporin between different studies (see Table 2). These discrepancies may arise from the use of different force-fields, water models, simulation protocols, simulation times, and insufficient sampling due to the limited time scale of all-atom MD simulations [31].…”

Section: Resultsmentioning

confidence: 99%

Molecular dynamics study of the archaeal aquaporin AqpM

et al. 2011

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BackgroundAquaporins are a large family of transmembrane channel proteins that are present throughout all domains of life and are implicated in human disorders. These channels, allow the passive but selective movement of water and other small neutral solutes across cell membranes. Aquaporins have been classified into two sub-families: i) strict aquaporins that only allow the passage of water and ii) the less selective aquaglyceroporins that transport water and other neutral solutes, such as glycerol, CO2 or urea. Recently, the identification and characterization of a number of archaeal and bacterial aquaporins suggested the existence of a third sub-family; one that is neither a strict aquaporin nor an aquaglyceroporin. The function and phylogeny of this third family is still a matter of debate.ResultsTwenty nanosecond molecular dynamics (MD) simulation of a fully hydrated tetramer of AqpM embedded in a lipid bilayer permitted predictions to be made of key biophysical parameters including: single channel osmotic permeability constant (pf), single channel diffusive permeability constant (pd), channel radius, potential water occupancy of the channel and water orientation inside the pore. These properties were compared with those of well characterized representatives of the two main aquaporin sub-families. Results show that changes in the amino acid composition of the aromatic/arginine region affect the size and polarity of the selectivity filter (SF) and could help explain the difference in water permeability between aquaporins. In addition, MD simulation results suggest that AqpM combines characteristics of strict aquaporins, such as the narrow SF and channel radius, with those of aquaglyceroporins, such as a more hydrophobic and less polar SF.ConclusionsMD simulations of AqpM extend previous evidence that this archaeal aquaporin exhibits hybrid features intermediate between the two known aquaporin sub-families, supporting the idea that it may constitute a member of a novel class of aquaporins.

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Human aquaporin 4 gating dynamics in dc and ac electric fields: A molecular dynamics study

Cited by 54 publications

References 57 publications

Evaluation of Protein Electrostatic Potential from Molecular Dynamics Simulations in the Presence of Exogenous Electric Fields: The Case Study of Myoglobin

Evaluation of Protein Electrostatic Potential from Molecular Dynamics Simulations in the Presence of Exogenous Electric Fields: The Case Study of Myoglobin

Structural Insight into Tetrameric hTRPV1 from Homology Modeling, Molecular Docking, Molecular Dynamics Simulation, Virtual Screening, and Bioassay Validations

Molecular dynamics study of the archaeal aquaporin AqpM

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