# Atomistic Insights into Anomeric and Stereochemical Effects on Glucose Transport by GLUTs

## TL;DR

This study reveals how glucose transporters prefer different glucose forms, showing that their binding sites have complex interactions that affect transport rates.

## Contribution

The study provides new mechanistic insights into the anomeric and stereochemical preferences of GLUT1 and GLUT3 for glucose transport.

## Key findings

- GLUT3 residues prefer α-d-glucose in extracellular regions and β-d-glucose in inward-facing regions.
- Anomeric stereoselectivity involves multiple extramembranous residues, not just the central binding site.
- Allosteric interactions contribute to cooperative transport behavior in mixed glucose simulations.

## Abstract

Although β-glucose
is more abundant than α-glucose
in aqueous solution, GLUT3 preferentially binds α-glucose due
to favorable interactions and conformational complementarity within
the protein binding site. This study explores the anomeric preferences
of glucose transporters GLUT1 and GLUT3 for α- and β-glucose
using classical MD, providing mechanistic insight into previously
reported differences in anomer-specific transport rates during net
influx, efflux, and exchange flux, as well as asymmetric binding of
glucose anomer derivatives. Analysis of hydrogen-bonding frequencies
between glucose anomers and transporter residues, combined with root
mean squared fluctuations (RMSF) of these residues during flooding
simulations, using either mixed α/β-glucose trajectories
or single-anomer trajectories, reveals distinct residue preferences
along the transport pathway. GLUT3 residues exposed to the extracellular
solution preferentially interact with α-d-glucose,
while inward-facing residues show a bias toward β-d-glucose. This distributed network of anomer-selective interactions,
particularly concentrated in extramembranous surface regions, highlights
previously unrecognized complexity in GLUT stereoselectivity. Enhanced
residue displacements adjacent to orthosteric glucose collision sites
suggest that allosteric intra- and interchain interactions may contribute
to the cooperative transport behavior observed in mixed α +
β-glucose simulations compared to single-anomer conditions.
Importantly, anomeric stereoselectivity in GLUT1 and GLUT3 is not
confined to the central high-affinity binding site, but also involves
a multiplicity of extramembranous residues, underscoring the broader
structural basis for selective glucose transport.