TY - JOUR
T1 - Multiple Interactions of Glucose with the Extra-Membranous Loops of GLUT1 Aid Transport
AU - Gonzalez-Resines, Saul
AU - Quinn, Peter J.
AU - Naftalin, Richard J.
AU - Domene, Carmen
N1 - Publisher Copyright:
© 2021 American Chemical Society.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/7/26
Y1 - 2021/7/26
N2 - Molecular dynamics simulations amounting to ≈8 μs demonstrate that the glucose transporter GLUT1 undergoes structural fluctuations mediated by the fluidity of the lipid bilayer and the proximity to glucose. The fluctuations of GLUT1 increase as the glucose concentration is raised. These fluctuations are more pronounced when the lipid bilayer is in the fluid compared to the gel phase. Glucose interactions are confined to the extra-membranous residues when the lipid is in the gel phase but diffuses into the transmembrane regions in the fluid phase. Proximity of glucose to GLUT1 causes asynchronous expansions of key bottlenecks at the internal and external openings of the central pore. This is accomplished only by small conformational changes at the single residue level that lower the resistance to glucose movements, thereby permitting unsteered glucose and water movements along the entire length of the pore. When glucose is near salt bridges located at the external and internal openings of the central pore, the distance separating the polar amino acid residues guarding these apertures tends to increase in both fluid and gel phases. It is evident that the multiplicity of glucose interactions, obtained with high concentrations, amplifies the structural fluctuations in GLUT1. The findings that most of the salt bridges and the bottlenecks appear to be operated by glucose proximity suggest that the main triggers to activation of transport are located within the solvent accessible linker regions in the extramembranous zones.
AB - Molecular dynamics simulations amounting to ≈8 μs demonstrate that the glucose transporter GLUT1 undergoes structural fluctuations mediated by the fluidity of the lipid bilayer and the proximity to glucose. The fluctuations of GLUT1 increase as the glucose concentration is raised. These fluctuations are more pronounced when the lipid bilayer is in the fluid compared to the gel phase. Glucose interactions are confined to the extra-membranous residues when the lipid is in the gel phase but diffuses into the transmembrane regions in the fluid phase. Proximity of glucose to GLUT1 causes asynchronous expansions of key bottlenecks at the internal and external openings of the central pore. This is accomplished only by small conformational changes at the single residue level that lower the resistance to glucose movements, thereby permitting unsteered glucose and water movements along the entire length of the pore. When glucose is near salt bridges located at the external and internal openings of the central pore, the distance separating the polar amino acid residues guarding these apertures tends to increase in both fluid and gel phases. It is evident that the multiplicity of glucose interactions, obtained with high concentrations, amplifies the structural fluctuations in GLUT1. The findings that most of the salt bridges and the bottlenecks appear to be operated by glucose proximity suggest that the main triggers to activation of transport are located within the solvent accessible linker regions in the extramembranous zones.
UR - http://www.scopus.com/inward/record.url?scp=85111228123&partnerID=8YFLogxK
U2 - 10.1021/acs.jcim.1c00310
DO - 10.1021/acs.jcim.1c00310
M3 - Article
AN - SCOPUS:85111228123
SN - 1549-9596
VL - 61
SP - 3559
EP - 3570
JO - JOURNAL OF CHEMICAL INFORMATION AND MODELING
JF - JOURNAL OF CHEMICAL INFORMATION AND MODELING
IS - 7
ER -