Investigation of molecular details of a bacterial cationic amino acid transporter (GkApcT) during arginine transportation using molecular dynamics simulation and umbrella sampling techniques.
Cationic amino acid transporters (CATs)
MD simulations
MM-PBSA
Umbrella sampling, Binding free energy
Journal
Journal of molecular modeling
ISSN: 0948-5023
Titre abrégé: J Mol Model
Pays: Germany
ID NLM: 9806569
Informations de publication
Date de publication:
21 Jul 2023
21 Jul 2023
Historique:
received:
01
05
2023
accepted:
17
07
2023
medline:
24
7
2023
pubmed:
22
7
2023
entrez:
21
7
2023
Statut:
epublish
Résumé
Cationic amino acid transporters (CATs) facilitate arginine transport across membranes and maintain its levels in various tissues and organs, but their overexpression has been associated with severe cancers. A recent study identified the alternating access mechanism and critical residues involved in arginine transportation in a cationic amino acid transporter from Geobacillus kaustophilus (GkApcT). Here, we used molecular dynamics (MD) simulation methods to investigate the transportation mechanism of arginine (Arg) through GkApcT. The results revealed that arginine strongly interacts with specific binding site residues (Thr43, Asp111, Glu115, Lys191, Phe231, Ile234, and Asp237). Based on the umbrella sampling, the main driving force for arginine transport is the polar interactions of the arginine with channel-lining residues. An in-depth description of the dissociation mechanism and binding energy analysis brings valuable insight into the interactions between arginine and transporter residues, facilitating the design of effective CAT inhibitors in cancer cells. The membrane-protein system was constructed by uploading the prokaryotic CAT (PDB ID: 6F34) to the CHARMM-GUI web server. Molecular dynamics simulations were done using the GROMACS package, version 5.1.4, with the CHARMM36 force field and TIP3P water model. The MM-PBSA approach was performed for determining the arginine binding free energy. Furthermore, the hotspot residues were identified through per-residue decomposition analysis. The characteristics of the channel such as bottleneck radius and channel length were analyzed using the CaverWeb 1.1 web server. The proton wire inside the transporter was investigated based on the classic Grotthuss mechanism. We also investigated the atomistic details of arginine transportation using the path-based free energy umbrella sampling technique (US).
Identifiants
pubmed: 37479900
doi: 10.1007/s00894-023-05670-w
pii: 10.1007/s00894-023-05670-w
doi:
Substances chimiques
Amino Acid Transport Systems, Basic
0
Arginine
94ZLA3W45F
Membrane Proteins
0
Membrane Transport Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
260Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
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