Collective domain motion facilitates water transport in SGLT1

Sever, Marko (author), Merzel, Franci (author)

The human sodium–glucose cotransporter protein (SGLT1) is an important representative of the sodium solute symporters belonging to the secondary active transporters that are critical to the homeostasis of sugar, sodium, and water in the cell. The underlying transport mechanism of SGLT1 is based on switching between inward- and outward-facing conformations, known as the alternating access model, which is crucial for substrate transport, and has also been postulated for water permeation. However, the nature of water transport remains unclear and is disputed along the passive and active transport, with the latter postulating the presence of the pumping effect. To better examine the water transport in SGLT1, we performed a series of equilibrium all-atom molecular dynamics simulations, totaling over 6 µs of sample representative conformational states of SGLT1 and its complexes, with the natural substrates, ions, and inhibitors. In addition to elucidating the basic physical factors influencing water permeation, such as channel openings and energetics, we focus on dynamic flexibility and its relationship with domain motion. Our results clearly demonstrate a dependence of instantaneous water flux on the channel opening and local water diffusion in the channel, strongly supporting the existence of a passive water transport in SGLT1. In addition, a strong correlation found between the local water diffusion and protein domain motion, resembling the “rocking-bundle” motion, reveals its facilitating role in the water transport.

• Language: English
• Keywords: molecular dynamics simulations, SGLT1 protein, transmembrane water transport, diffusion, intrinsic domain motion, principal component analysis
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2023
• Number of pages: 15 str.
• Numbering: Vol. 24, iss. 13, art. 10528
• PID: 20.500.12556/RUL-164852
• UDC: 577
• ISSN on article: 1422-0067
• DOI: 10.3390/ijms241310528
• COBISS.SI-ID: 158078723
• Publication date in RUL: 13.11.2024

Record is a part of a journal

• Title: International journal of molecular sciences
• Shortened title: Int. j. mol. sci.
• Publisher: MDPI
• ISSN: 1422-0067
• COBISS.SI-ID: 2779162

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: biokemija, glukozni kotransporter, prenašalci, sladkor, natrij, voda, celice

Projects

• Funder: ARRS - Slovenian Research Agency
• Project number: P1-0010
• Name: Folding in dinamika biomolekularnih sistemov