Enhanced Sampling Molecular Dynamics Simulations Reveal Transport Mechanism of Glycoconjugate Drugs through GLUT1.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Molecular Dynamics Simulation* ; Glucose Transporter Type 1*/metabolism ; Glucose Transporter Type 1*/chemistry ; Glycoconjugates*/metabolism ; Glycoconjugates*/chemistry; Humans ; Glucose/metabolism ; Biological Transport ; Thermodynamics

Glucose transporters GLUT1 belong to the major facilitator superfamily and are essential to human glucose uptake. The overexpression of GLUT1 in tumor cells designates it as a pivotal target for glycoconjugate anticancer drugs. However, the interaction mechanism of glycoconjugate drugs with GLUT1 remains largely unknown. Here, we employed all-atom molecular dynamics simulations, coupled to steered and umbrella sampling techniques, to examine the thermodynamics governing the transport of glucose and two glycoconjugate drugs (i.e., 6-D-glucose-conjugated methane sulfonate and 6-D-glucose chlorambucil) by GLUT1. We characterized the specific interactions between GLUT1 and substrates at different transport stages, including substrate recognition, transport, and releasing, and identified the key residues involved in these procedures. Importantly, our results described, for the first time, the free energy profiles of GLUT1-transporting glycoconjugate drugs, and demonstrated that H160 and W388 served as important gates to regulate their transport via GLUT1. These findings provide novel atomic-scale insights for understanding the transport mechanism of GLUT1, facilitating the discovery and rational design of GLUT1-targeted anticancer drugs.

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2023YFC3403502 National Key Research and Development Program; 32301041 National Natural Science Foundation of China; 2023HWYQ-044 Shandong Excellent Young Scientists (Overseas) Fund Program; ZR2022QC014 Natural Science Foundation of Shandong Province

Keywords: GLUT1; anticancer drug; glycoconjugate; molecular dynamics simulations; transport mechanism

0 (Glucose Transporter Type 1)
0 (Glycoconjugates)
IY9XDZ35W2 (Glucose)
0 (SLC2A1 protein, human)

Date Created: 20240525 Date Completed: 20240525 Latest Revision: 20240813

20250114

PMC11122603

10.3390/ijms25105486

38791523