Induced polarization in MD simulations of the 5HT3 receptor channel

Journal of the American Chemical Society American Chemical Society 142:20 (2020) 9415-9427

Authors:

Stephen Tucker, Mark Sansom

Abstract:

Ion channel proteins form water-filled nanoscale pores within lipid bilayers and their properties are dependent on the complex behavior of water in a nano-confined environment. Using a simplified model of the pore of the 5HT3 receptor (5HT3R) which restrains the backbone structure to that of the parent channel protein from which it is derived we compare additive with polarizable models in describing the behavior of water in nanopores. Molecular Dynamics simulations were performed with four conformations of the channel: two closed state structures, an intermediate state, and an open state, each embedded in a phosphatidylcholine bilayer. Water density profiles revealed that for all water models, the closed and intermediate states exhibited strong dewetting within the central hydrophobic gate region of the pore. However, the open state conformation exhibited varying degrees of hydration, ranging from partial wetting for the TIP4P/2005 water model, to complete wetting for the polarizable AMOEBA14 model. Water dipole moments calculated using polarizable force fields also revealed that water molecules remaining within dewetted sections of the pore resemble gas phase water. Free energy profiles for Na+ and for Cl- ions within the open state pore revealed more rugged energy landscapes using polarizable force fields, and the hydration number profiles of these ions were also sensitive to induced polarization resulting in a substantive reduction of the number of waters within the first hydration shell of Cl- whilst it permeates the pore. These results demonstrate that induced polarization can influence the complex behavior of water and ions within nanoscale pores and provides important new insights into their chemical properties.

Publisher Correction: Structure and assembly of calcium homeostasis modulator proteins.

Nature structural & molecular biology 27:3 (2020) 305

Authors:

Johanna L Syrjanen, Kevin Michalski, Tsung-Han Chou, Timothy Grant, Shanlin Rao, Noriko Simorowski, Stephen J Tucker, Nikolaus Grigorieff, Hiro Furukawa

Abstract:

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Annotating Ion Channel Pores: Structures, Hydrophobicity and the Threshold for Permeation

Biophysical Journal Elsevier 118:3 (2020) 272a

Authors:

Shanlin Rao, Gianni Klesse, Stephen J Tucker, Mark SP Sansom

Structure and assembly of calcium homeostasis modulator proteins.

Nat Struct Mol Biol 27:2 (2020) 150-159

Authors:

Johanna L Syrjanen, Kevin Michalski, Tsung-Han Chou, Timothy Grant, Shanlin Rao, Noriko Simorowski, Stephen J Tucker, Nikolaus Grigorieff, Hiro Furukawa

Abstract:

The biological membranes of many cell types contain large-pore channels through which a wide variety of ions and metabolites permeate. Examples include connexin, innexin and pannexin, which form gap junctions and/or bona fide cell surface channels. The most recently identified large-pore channels are the calcium homeostasis modulators (CALHMs), through which ions and ATP permeate in a voltage-dependent manner to control neuronal excitability, taste signaling and pathologies of depression and Alzheimer's disease. Despite such critical biological roles, the structures and patterns of their oligomeric assembly remain unclear. Here, we reveal the structures of two CALHMs, chicken CALHM1 and human CALHM2, by single-particle cryo-electron microscopy (cryo-EM), which show novel assembly of the four transmembrane helices into channels of octamers and undecamers, respectively. Furthermore, molecular dynamics simulations suggest that lipids can favorably assemble into a bilayer within the larger CALHM2 pore, but not within CALHM1, demonstrating the potential correlation between pore size, lipid accommodation and channel activity.

Induced Polarization in MD Simulations of the 5HT3 Receptor Channel

(2020)

Authors:

Gianni Klesse, Shanlin Rao, Stephen Tucker, Mark SP Sansom

Abstract:

Ion channel proteins form water-filled nanoscale pores within lipid bilayers and their properties are dependent on the complex behavior of water in a nano-confined environment. Using the pore of the 5HT3 receptor (5HT3R) we compare additive with polarizable models in describing the behavior of water in nanopores. Molecular Dynamics simulations were performed with four conformations of the channel: two closed state structures, an intermediate state, and an open state, each embedded in a phosphatidylcholine bilayer. Water density profiles revealed that for all water models, the closed and intermediate states exhibited strong dewetting within the central hydrophobic gate region of the pore. However, the open state conformation exhibited varying degrees of hydration, ranging from partial wetting for the TIP4P/2005 water model, to complete wetting for the polarizable AMOEBA14 model. Water dipole moments calculated using polarizable force fields also revealed that water molecules remaining within dewetted sections of the pore resemble gas phase water. Free energy profiles for Na+ and for Cl− ions within the open state pore revealed more rugged energy landscapes using polarizable force fields, and the hydration number profiles of these ions were also sensitive to induced polarization resulting in a substantive reduction of the number of waters within the first hydration shell of Cl− whilst it permeates the pore. These results demonstrate that induced polarization can influence the complex behavior of water and ions within nanoscale pores and provides important new insights into their chemical properties.

ToC Graphic