Molecular Basis of GLUT4 in Glucose Transport: Atomistic Molecular Dynamics Study

Abstract

The glucose transporter 4 (GLUT4) is one of the most important glucose transporter proteins for the absorption of glucose from the plasma circulation after a meal or during exercise. It is present in skeletal muscle, adipose tissue cells, cardiac muscle, and it has also been found in brain cells. It plays a significant role in the development of various diseases such as type 2 diabetes, cancer, and cardiac diseases. Inside a cell, GLUT4 is transported towards the cell membrane upon an insulin stimulus, leading to a 10- to 40-fold increase in the glucose uptake. In spite of its importance, the molecular mechanism of glucose transport by GLUT4 is still not clear. There is no crystal structure available for the GLUT4 protein either. However, using existing structural information of the other solved glucose transporter structures, we have modeled and validated the GLUT4 structure in three conformations: the outward-open, outward-occluded, and inward-open conformation. The GLUT4 models with glucose bound were subsequently embedded in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) membrane and simulated over microsecond time scales using unbiased atomistic molecular dynamics simulations. In addition, we also carried out random acceleration molecular dynamics simulations to explore all possible pathways for glucose transport across the membrane. Our simulation studies revealed specific GLUT4 residues that captured the conformational changes in GLUT4 structure on glucose binding. Overall, the study provides atomistic level structural information on glucose transport and also provides one with ideas for the development of therapeutic agents blocking the function of GLUT4. This development work is important given that cancer cells express elevated levels of glucose transporter proteins and depend on increased glucose uptake for proliferation.