Gibbs Free-Energy Gradient along the Path of Glucose
Transport through Human Glucose Transporter 3
Version 2 2018-07-13, 17:22
Version 1 2018-06-11, 12:51
Posted on 2018-07-13 - 17:22
Fourteen
glucose transporters (GLUTs) play essential roles in human
physiology by facilitating glucose diffusion across the cell membrane.
Due to its central role in the energy metabolism of the central nervous
system, GLUT3 has been thoroughly investigated. However, the Gibbs
free-energy gradient (what drives the facilitated diffusion of glucose)
has not been mapped out along the transport path. Some fundamental
questions remain. Here we present a molecular dynamics study of GLUT3
embedded in a lipid bilayer to quantify the free-energy profile along
the entire transport path of attracting a β-d-glucose
from the interstitium to the inside of GLUT3 and, from there, releasing
it to the cytoplasm by Arrhenius thermal activation. From the free-energy
profile, we elucidate the unique Michaelis–Menten characteristics
of GLUT3, low KM and high VMAX, specifically suitable for neurons’ high and
constant demand of energy from their low-glucose environments. We
compute GLUT3’s binding free energy for β-d-glucose
to be −4.6 kcal/mol in agreement with the experimental value
of −4.4 kcal/mol (KM = 1.4 mM).
We also compute the hydration energy of β-d-glucose,
−18.0 kcal/mol vs the experimental data, −17.8 kcal/mol.
In this, we establish a dynamics-based connection from GLUT3’s
crystal structure to its cellular thermodynamics with quantitative
accuracy. We predict equal Arrhenius barriers for glucose uptake and
efflux through GLUT3 to be tested in future experiments.
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Liang, Huiyun; Bourdon, Allen K.; Chen, Liao Y.; Phelix, Clyde F.; Perry, George (2018). Gibbs Free-Energy Gradient along the Path of Glucose
Transport through Human Glucose Transporter 3. ACS Publications. Collection. https://doi.org/10.1021/acschemneuro.8b00223
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AUTHORS (5)
HL
Huiyun Liang
AB
Allen K. Bourdon
LC
Liao Y. Chen
CP
Clyde F. Phelix
GP
George Perry