Metadynamics simulations reveal a Na+ independent exiting path of galactose for the inward-facing conformation of vSGLT

Autor: Alex Rodriguez, Alessandra Magistrato, Ina Bisha, Alessandro Laio
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Computer and Information Sciences
Sodium
chemistry.chemical_element
Cooperativity
Gating
Molecular Dynamics Simulation
chemistry
Sodium-Glucose Transport Proteins
Cellular and Molecular Neuroscience
chemistry.chemical_compound
Genetics
Electrochemical gradient
Molecular Biology
lcsh:QH301-705.5
Ecology
Evolution
Behavior and Systematics
Ion transporter
Ecology
Metadynamics
Galactose
Biology and Life Sciences
molecular dynamics
Kinetics
Computational Theory and Mathematics
Biochemistry
lcsh:Biology (General)
galactose
sodium
sodium glucose cotransporter
chemistry
kinetics
metabolism
molecular dynamics
thermodynamics
Galactose
Kinetics
Molecular Dynamics Simulation
Sodium
Sodium-Glucose Transport Proteins
Thermodynamics
Modeling and Simulation
Symporter
Biophysics
Thermodynamics
sodium glucose cotransporter
metabolism
Research Article
Zdroj: PLoS Computational Biology, Vol 10, Iss 12, p e1004017 (2014)
PLoS Computational Biology
PLoS computational biology 10 (2014). doi:10.1371/journal.pcbi.1004017
info:cnr-pdr/source/autori:Bisha, Ina; Rodriguez, Alex; Laio, Alessandro; Magistrato, Alessandra/titolo:Metadynamics Simulations Reveal a Na+ Independent Exiting Path of Galactose for the Inward-Facing Conformation of vSGLT/doi:10.1371%2Fjournal.pcbi.1004017/rivista:PLoS computational biology/anno:2014/pagina_da:/pagina_a:/intervallo_pagine:/volume:10
ISSN: 1553-7358
Popis: Sodium-Galactose Transporter (SGLT) is a secondary active symporter which accumulates sugars into cells by using the electrochemical gradient of Na+ across the membrane. Previous computational studies provided insights into the release process of the two ligands (galactose and sodium ion) into the cytoplasm from the inward-facing conformation of Vibrio parahaemolyticus sodium/galactose transporter (vSGLT). Several aspects of the transport mechanism of this symporter remain to be clarified: (i) a detailed kinetic and thermodynamic characterization of the exit path of the two ligands is still lacking; (ii) contradictory conclusions have been drawn concerning the gating role of Y263; (iii) the role of Na+ in modulating the release path of galactose is not clear. In this work, we use bias-exchange metadynamics simulations to characterize the free energy profile of the galactose and Na+ release processes toward the intracellular side. Surprisingly, we find that the exit of Na+ and galactose is non-concerted as the cooperativity between the two ligands is associated to a transition that is not rate limiting. The dissociation barriers are of the order of 11–12 kcal/mol for both the ion and the substrate, in line with kinetic information concerning this type of transporters. On the basis of these results we propose a branched six-state alternating access mechanism, which may be shared also by other members of the LeuT-fold transporters.
Author Summary Membrane proteins are crucial for the communication of the cell with the environment. Among these, symporters are in charge of the transport of molecules (like sugars, amino acids, osmolytes) inside the cells, exploiting the concentration gradient of an ion to perform the task. Here we investigate by atomistic simulations the transport mechanism of the Sodium-Galactose symporter. Our results allow constructing a detailed and quantitative model of the release process of the two ligands. Surprisingly, we find that the galactose is released to the cytosol independently from the ion, unambiguously indicating that the coupling in their transport mechanism is associated to the steps preceding the release process. A large family of symporters shares the same fold and potentially the same transport mechanism. As such our results are important also because they can provide insights on common mechanistic features of these transporters.
Databáze: OpenAIRE
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