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 |
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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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