Dataset Information

Capturing Functional Motions of Membrane Channels and Transporters with Molecular Dynamics Simulation.

ABSTRACT: Conformational changes of proteins are involved in all aspects of protein function in biology. Almost all classes of proteins respond to changes in their environment, ligand binding, and interaction with other proteins and regulatory agents through undergoing conformational changes of various degrees and magnitudes. Membrane channels and transporters are the major classes of proteins that are responsible for mediating efficient and selective transport of materials across the cellular membrane. Similar to other proteins, they take advantage of conformational changes to make transitions between various functional states. In channels, large-scale conformational changes are mostly involved in the process of "gating", i.e., opening and closing of the pore of the channel protein in response to various signals. In transporters, conformational changes constitute various steps of the conduction process, and, thus, are more closely integrated in the transport process. Owing to significant progress in developing highly efficient parallel algorithms in molecular dynamics simulations and increased computational resources, and combined with the availability of high-resolution, atomic structures of membrane proteins, we are in an unprecedented position to use computer simulation and modeling methodologies to investigate the mechanism of function of membrane channels and transporters. While the entire transport cycle is still out of reach of current methodologies, many steps involved in the function of transport proteins have been characterized with molecular dynamics simulations. Here, we present several examples of such studies from our laboratory, in which functionally relevant conformational changes of membrane channels and transporters have been characterized using extended simulations.

SUBMITTER: Shaikh S

PROVIDER: S-EPMC3661405 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Capturing Functional Motions of Membrane Channels and Transporters with Molecular Dynamics Simulation.

Shaikh Saher S Wen Po-Chao PC Enkavi Giray G Huang Zhijian Z Tajkhorshid Emad E

Journal of computational and theoretical nanoscience 20101201 12

Conformational changes of proteins are involved in all aspects of protein function in biology. Almost all classes of proteins respond to changes in their environment, ligand binding, and interaction with other proteins and regulatory agents through undergoing conformational changes of various degrees and magnitudes. Membrane channels and transporters are the major classes of proteins that are responsible for mediating efficient and selective transport of materials across the cellular membrane. S ...[more]

PMID: 23710155

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Project description:Transient receptor potential vanilloid subtype 1 (TRPV1) is a heat-sensitive ion channel also involved in pain sensation, and is the receptor for capsaicin, the active ingredient of hot chili peppers. The recent structures of TRPV1 revealed putative ligand density within the S1 to S4 voltage-sensor-like domain of the protein. However, questions remain regarding the dynamic role of the lipid bilayer in ligand binding to TRPV1. Molecular dynamics simulations were used to explore behavior of capsaicin in a 1-palmitoyl-2-oleoyl phosphatidylcholine bilayer and with the target S1-S4 transmembrane helices of TRPV1. Equilibrium simulations reveal a preferred interfacial localization for capsaicin. We also observed a capsaicin molecule flipping from the extracellular to the intracellular leaflet, and subsequently able to access the intracellular TRPV1 binding site. Calculation of the potential of mean force (i.e., free energy profile) of capsaicin along the bilayer normal confirms that it prefers an interfacial localization. The free energy profile indicates that there is a nontrivial but surmountable barrier to the flipping of capsaicin between opposing leaflets of the bilayer. Molecular dynamics of the S1-S4 transmembrane helices of the TRPV1 in a lipid bilayer confirm that Y511, known to be crucial to capsaicin binding, has a distribution along the bilayer normal similar to that of the aromatic group of capsaicin. Simulations were conducted of the TRPV1 S1-S4 transmembrane helices in the presence of capsaicin placed in the aqueous phase, in the lipid, or docked to the protein. No stable interaction between ligand and protein was seen for simulations initiated with capsaicin in the bilayer. However, interactions were seen between TRPV1 and capsaicin starting from the cytosolic aqueous phase, and capsaicin remained stable in the majority of simulations from the docked pose. We discuss the significance of capsaicin flipping from the extracellular to the intracellular leaflet and mechanisms of binding site access by capsaicin.

Dataset Information

Capturing Functional Motions of Membrane Channels and Transporters with Molecular Dynamics Simulation.

Publications

Capturing Functional Motions of Membrane Channels and Transporters with Molecular Dynamics Simulation.

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