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Glucose transporters (GLUTs), expressed in all types of human cells, are responsible for the uptake of sugars as the primary energy source for the normal functions of good cells and for the abnormal growth of cancer cells. The E. coli xylose permease (XylE), a homologue of human GLUTs, has been investigated more thoroughly than other major facilitator proteins in the current literature. In this paper, we present a molecular dynamics (MD) study of an all-atom model system to elucidate the atomistic details and the free-energy landscape along the path of binding a xylopyranose (XYP) from the extracellular space to the inside of the transporter protein XylE. From the MD simulations, the Gibbs free energy of binding was found to be − 4.4 kcal/mol in agreement with the experimental value of − 4.7 kcal/mol. The accuracy of our study is further shown in the computed hydration energy of XYP of − 14.6 kcal/mol in comparison with the experimental data of − 15.0 kcal/mol. Along the binding path, the Gibbs free energy of the XYP-XylE complex first rises from zero in the dissociated state to approximately 4 kcal/mol in the transition state (when XylE slightly increases its opening toward the extracellular side to accommodate XYP) before dropping down to − 9.0 kcal/mol in the bound state. These quantitative insights indicate the fast equilibration between the bound and the unbound states of XylE and XYP. They also serve as an atomistic-dynamic corroboration of the experimental conclusion that XylE is a high-affinity sugar transporter. [ABSTRACT FROM AUTHOR]

Glucose transporter GLUT1 is ubiquitously expressed in the human body from the red cells to the blood-brain barrier to the skeletal muscles. It is physiologically relevant to understand how GLUT1 facilitates diffusion of glucose across the cell membrane. It is also pathologically relevant because GLUT1 deficiency causes neurological disorders and anemia and because GLUT1 overexpression fuels the abnormal growth of cancer cells. This article presents a quantitative investigation of GLUT1 based on all-atom molecular-dynamics (MD) simulations of the transporter embedded in lipid bilayers of asymmetric inner-and-outer-leaflet lipid compositions, subject to asymmetric intra-and-extra-cellular environments. This is in contrast with the current literature of MD studies that have not considered both of the aforementioned asymmetries of the cell membrane. The equilibrium (unbiased) dynamics of GLUT1 shows that it can facilitate glucose diffusion across the cell membrane without undergoing large-scale conformational motions. The Gibbs free-energy profile, which is still lacking in the current literature of GLUT1, quantitatively characterizes the diffusion path of glucose from the periplasm, through an extracellular gate of GLUT1, on to the binding site, and off to the cytoplasm. This transport mechanism is validated by the experimental data that GLUT1 has low water-permeability, uptake-efflux symmetry, and 10 kcal/mol Arrhenius activation barrier around 37 °C. [Display omitted] • Model system of two membrane patches asymmetric in EC and IC salines • Model RBC membrane asymmetric in inner and outer leaflet lipid compositions • EC-gating mechanism of GLUT1 in quantitative agreement with in vitro data on glucose transport and water permeation [ABSTRACT FROM AUTHOR]

Plasmodium falciparum aquaporin (PfAQP) is a multifunctional channel protein in the plasma membrane of the malarial parasite that causes the most severe form of malaria infecting more than a million people a year. This channel protein facilitates transport of water and several solutes across the cell membrane. In order to better elucidate the fundamental interactions between PfAQP and its permeants and among the permeants, I conducted over three microseconds in silico experiments of atomistic models of the PfAQP–membrane system to obtain the free-energy profiles of five permeants (erythritol, water, glycerol, urea, and ammonia) throughout the amphipathic conducting pore of PfAQP. The profiles are analyzed in light of and shown to be consistent with the existent in vitro data. The binding affinities are computed using the free-energy profiles and the permeant fluctuations inside the channel. On this basis, it is predicted that erythritol, a permeant of PfAQP itself having a deep ditch in its permeation passageway, inhibits PfAQP's functions of transporting water and other solutes with an IC 50 in the range of high nanomolars. This leads to the possibility that erythritol, a sweetener generally considered safe, may inhibit or kill the malarial parasite in vivo without causing undesired side effects. Experimental studies are hereby called for to directly test this theoretical prediction of erythritol strongly inhibiting PfAQP in vitro and possibly inhibiting P. falciparum in vivo . [ABSTRACT FROM AUTHOR]

Abstract For its fundamental relevance, transport of water and glycerol across the erythrocyte membrane has long been investigated before and after the discovery of aquaporins (AQPs), the membrane proteins responsible for water and glycerol transport. AQP1 is abundantly expressed in the human erythrocyte for maintaining its hydrohomeostasis where AQP3 is also expressed (at a level ~30-folds lower than AQP1) facilitating glycerol transport. This research is focused on two of the remaining questions: How permeable is AQP3 to water? What is the glycerol-AQP3 affinity under near-physiological conditions? Through atomistic modelling and large-scale simulations, we found that AQP3 is two to three times more permeable to water than AQP1 and that the glycerol-AQP3 affinity is approximately 500/M. Using these computed values along with the data from the latest literature on AQP1 and on erythrocyte proteomics, we estimated the water and glycerol transport rates across the membrane of an entire erythrocyte. We used these rates to predict the time courses of erythrocyte swelling-shrinking in response to inward and outward osmotic gradients. Experimentally, we monitored the time course of human erythrocytes when subject to an osmotic or glycerol gradient with light scattering in a stopped-flow spectrometer. We observed close agreement between the experimentally measured and the computationally predicted time courses of erythrocytes, which corroborated our computational conclusions on the AQP3 water-permeability and the glycerol-AQP3 affinity. Graphical abstract Unlabelled Image Highlights • Human Aquaporin 3 is functionally similar to its bacterium and parasite analogues. • Aquaporin 3, a glycerol channel, is more permeable than Aquaporin 1. • Aquaporin 3 has an affinity of 500/M for glycerol. [ABSTRACT FROM AUTHOR]