2021 International Conference on Biomedical and Bioinformatics Engineering (ICBBE 2021)
Prof. Richard Naftalin

Home

Speech title:

What can we learn about the mechanism of glucose transport via GLUT1 from molecular dynamics simulations?

Abstract:

Richard J. Naftalin1, Saul Gonzalez-Resines2, Peter Quinn3 and Carmen Domene2,4.

 1BHF Centre of Research Excellence, School of Medicine and Life Sciences, King’s College London

2Departments of Chemistry University of Bath, United Kingdom

3Department of Biochemistry, King’s College London, London, United Kingdom

4Chemistry Research Laboratory, Mansfield Road, University of Oxford, United Kingdom

 

Glucose transport across cell membranes is facilitated by membrane transporter proteins with ligand selectivity and temperature sensitivity.  In some glucose transporters, GLUTs 1 and 3, accelerated exchange occurs between labelled and unlabelled glucose in the opposing bathing solutions.  Recent elucidation of the 3D structures of these transporter proteins permits simulations of glucose trajectories in these transporters at atomistic levels, using high performance computers.  This has clarified several issues relating to the mechanism of glucose transport.

 

Molecular dynamics simulations amounting ≈ 8 µs, in the glucose transporter, SCL2A.1 (GLUT1) demonstrate that undergoes structural fluctuations mediated by the fluidity of the lipid bilayer and its proximity to D-glucose {1,2}.  GLUT1 fluctuations increase with raised glucose concentration and are more pronounced when the lipid bilayer is fluid, in comparison to the gel state.  In the gel state glucose H-bonding interactions are confined to the extra-membranous residues of GLUT1 but penetrate into the transmembrane regions when the membrane is in the fluid state.

 

It is evident from root mean square fluctuations (RMSFs) that the multiplicity of glucose H-bonding interactions  obtaining during exposure to high ligand concentrations amplify the structural fluctuations in GLUT1.  

 

Glucose proximity expands the bottlenecks at the internal and external openings of GLUT1’s central pore.  These transient dilatations are accomplished only with small conformational changes at single residue level and reduce the gating resistance to glucose movements.  This allows unbiased  glucose and water movements along the full extent of the pore.  Also, when glucose is close to several of the salt bridges located in the extramembranous linker regions that guard  the external and internal openings of the central pore, the separation distance between the polar amino acid residues tends to increase.  

 

These new findings, showing that gating of glucose access to the central regions of the transporter is  mainly operated by glucose proximity, suggest that the key triggers to transport activation are located within the solvent accessible linker regions in the extramembranous zones, rather than at the high affinity central binding site.

 

Molecular dynamic simulations also demonstrate simultaneous exchanges between adjacent D-glucose ligands within GLUT1.  These exchanges occur at both external and internal solution-protein interfaces and in the  large central vestibule.   These interchanges in glucose position within the vestibule encompass along the Z-axis occur in  time periods  ranging from 2- 20 ns.  The exchanges at the solution protein-interfaces  involve more rapid displacements of H-bonded glucose by glucose from the external solutions.   

 These demonstrations of simultaneous glucose exchange between adjacent ligands illustrate that the accelerated exchange process within GLUTs is consistent with a fixed multisite model for glucose transport. Glucose ligands move independently, stochastically, and simultaneously  within the transporter tunnels and channels, and can exchange simultaneously, rather than as a “ping-pong,” sequential process, as envisaged by the alternate access hypothesis for exchange transport.  

These new findings imply the glucose exchanges occurs more frequently when the transport pathway is congested by  bottleneck closures that result in  glucose accumulation in the central vestibule and explains why glucose exchange is relatively faster than net flux at lower temperatures, when bottleneck closure is more frequent.   

1) Iglesias-Fernandez, J. et al. (2017) ‘Membrane Phase-Dependent Occlusion of Intramolecular GLUT1 Cavities Demonstrated by Simulations’, Biophysical Journal., 112(6), pp. 1176–1184.

2) Gonzalez-Resines, S. et al. (2021) ‘Multiple Interactions of Glucose with the Extra-Membranous Loops of GLUT1 Aid Transport’, Journal of Chemical Information and Modeling, 61(7), pp. 3559–3570.