Gibbs Free-Energy Gradient along the Path of Glucose Transport through Human Glucose Transporter 3

[Image: see text] 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 K(M) and high V(MAX), 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 (K(M) = 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.