Channelrhodopsin-2 Function is Modulated by Residual Hydrophobic Mismatch with the Surrounding Lipid Environment

Richards, Ryan; Mondal, Sayan; Weinstein, Harel; Dempski, Robert E.

doi:10.3390/app9132674

Title: Channelrhodopsin-2 Function is Modulated by Residual Hydrophobic Mismatch with the Surrounding Lipid Environment

Abstract

Channelrhodopsin-2 (ChR2) is a light-gated ion channel that conducts cations of multiple valencies down the electrochemical gradient. This light-gated property has made ChR2 a popular tool in the field of optogenetics, allowing for the spatial and temporal control of excitable cells with light. A central aspect of protein function is the interaction with the surrounding lipid environment. To further explore these membrane-protein interactions, we demonstrate the role of residual hydrophobic mismatch (RHM) as a mechanistically important component of ChR2 function. We combined computational and functional experiments to understand how RHM between the lipid environment and ChR2 alters the structural and biophysical properties of the channel. Analysis of our results revealed significant RHM at the intracellular/lipid interface of ChR2 from a triad of residues. The resulting energy penalty is substantial and can be lowered via mutagenesis to evaluate the functional effects of this change in lipid-protein interaction energy. The experimental measurement of channel stability, conductance and selectivity resulting from the reduction of the RHM energy penalty showed changes in progressive H+ permeability, kinetics and open-state stability, suggesting how the modulation of ChR2 by the surrounding lipid membrane can play an important biological role and contribute to the design of targeted optogeneticmore » constructs for specific cell types.« less

Authors:

Richards, Ryan; Mondal, Sayan;

; Dempski, Robert E.

Publication Date:: 2019-06-30

Sponsoring Org.:: USDOE

OSTI Identifier:: 1530465

Grant/Contract Number:: AC02- 05CH11231

Resource Type:: Published Article

Journal Name:: Applied Sciences

Additional Journal Information:: Journal Name: Applied Sciences Journal Volume: 9 Journal Issue: 13; Journal ID: ISSN 2076-3417

Publisher:: MDPI AG

Country of Publication:: Switzerland

Language:: English

Citation Formats


                    Richards, Ryan, Mondal, Sayan, Weinstein, Harel, and Dempski, Robert E. Channelrhodopsin-2 Function is Modulated by Residual Hydrophobic Mismatch with the Surrounding Lipid Environment.  Switzerland: N. p., 2019. 
Web.  doi:10.3390/app9132674.

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                    Richards, Ryan, Mondal, Sayan, Weinstein, Harel, & Dempski, Robert E. Channelrhodopsin-2 Function is Modulated by Residual Hydrophobic Mismatch with the Surrounding Lipid Environment.  Switzerland.  https://doi.org/10.3390/app9132674

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                    Richards, Ryan, Mondal, Sayan, Weinstein, Harel, and Dempski, Robert E. Sun .  
"Channelrhodopsin-2 Function is Modulated by Residual Hydrophobic Mismatch with the Surrounding Lipid Environment".  Switzerland.  https://doi.org/10.3390/app9132674.

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@article{osti_1530465,

  title        = {Channelrhodopsin-2 Function is Modulated by Residual Hydrophobic Mismatch with the Surrounding Lipid Environment},

  author       = {Richards, Ryan and Mondal, Sayan and Weinstein, Harel and Dempski, Robert E.},

  abstractNote = {Channelrhodopsin-2 (ChR2) is a light-gated ion channel that conducts cations of multiple valencies down the electrochemical gradient. This light-gated property has made ChR2 a popular tool in the field of optogenetics, allowing for the spatial and temporal control of excitable cells with light. A central aspect of protein function is the interaction with the surrounding lipid environment. To further explore these membrane-protein interactions, we demonstrate the role of residual hydrophobic mismatch (RHM) as a mechanistically important component of ChR2 function. We combined computational and functional experiments to understand how RHM between the lipid environment and ChR2 alters the structural and biophysical properties of the channel. Analysis of our results revealed significant RHM at the intracellular/lipid interface of ChR2 from a triad of residues. The resulting energy penalty is substantial and can be lowered via mutagenesis to evaluate the functional effects of this change in lipid-protein interaction energy. The experimental measurement of channel stability, conductance and selectivity resulting from the reduction of the RHM energy penalty showed changes in progressive H+ permeability, kinetics and open-state stability, suggesting how the modulation of ChR2 by the surrounding lipid membrane can play an important biological role and contribute to the design of targeted optogenetic constructs for specific cell types.},

  doi          = {10.3390/app9132674},

  journal      = {Applied Sciences},

  number       = 13,

  volume       = 9,

  place        = {Switzerland},

  year         = {2019},

  month        = {6}

}

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Title: Channelrhodopsin-2 Function is Modulated by Residual Hydrophobic Mismatch with the Surrounding Lipid Environment

Abstract

Citation Formats

Two Open States with Progressive Proton Selectivities in the Branched Channelrhodopsin-2 Photocycle journal, March 2010

Functional mechanisms of neurotransmitter transporters regulated by lipid–protein interactions of their terminal loops journal, September 2015

Computational Optogenetics: Empirically-Derived Voltage- and Light-Sensitive Channelrhodopsin-2 Model journal, September 2013

Channelrhodopsin-1: A Light-Gated Proton Channel in Green Algae journal, June 2002

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Millisecond-timescale, genetically targeted optical control of neural activity journal, August 2005

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Re-Introduction of Transmembrane Serine Residues Reduce the Minimum Pore Diameter of Channelrhodopsin-2 journal, November 2012

Spontaneous Inward Opening of the Dopamine Transporter Is Triggered by PIP 2 -Regulated Dynamics of the N-Terminus journal, August 2015

Time-Resolved Detection of Transient Movement of Helices F and G in Doubly Spin-Labeled Bacteriorhodopsin journal, June 2001

A GIPC1-Palmitate Switch Modulates Dopamine Drd3 Receptor Trafficking and Signaling journal, January 2016

Role of Annular Lipids in the Functional Properties of Leucine Transporter LeuT Proteomicelles journal, February 2016

A Usual G-Protein-Coupled Receptor in Unusual Membranes journal, December 2015

How structural elements evolving from bacterial to human SLC6 transporters enabled new functional properties journal, March 2018

Molecular Dynamics of Channelrhodopsin at the Early Stages of Channel Opening journal, June 2015

Free-energy determinants of alpha-helix insertion into lipid bilayers journal, April 1996

Photocycles of Channelrhodopsin-2 journal, January 2009

Cysteine Substitution and Labeling Provide Insight into Channelrhodopsin-2 Ion Conductance journal, September 2015

The Preference of Tryptophan for Membrane Interfaces † journal, October 1998

Energetics of Inclusion-Induced Bilayer Deformations journal, April 1998

Laser-evoked synaptic transmission in cultured hippocampal neurons expressing channelrhodopsin-2 delivered by adeno-associated virus journal, October 2009

Computational modeling of the N-terminus of the human dopamine transporter and its interaction with PIP 2 -containing membranes : Modeling of DAT N-Terminus/PIP journal, March 2015

Differential modification of the phospholipid profile by transient ischemia in rat hippocampal CA1 and CA3 regions journal, April 2013

The lipid composition of isolated brain cells and axons journal, January 1975

Phosphatidylinositol 4,5-bisphosphate, cholesterol, and fatty acids modulate the calcium-activated chloride channel TMEM16A (ANO1) journal, March 2018

Bi-stable neural state switches journal, December 2008

Escape Behavior Elicited by Single, Channelrhodopsin-2-Evoked Spikes in Zebrafish Somatosensory Neurons journal, August 2008

Optogenetic control of heart muscle in vitro and in vivo journal, October 2010

Modeling and Engineering aspects of ChannelRhodopsin2 System for Neural Photostimulation conference, August 2006

Ligand-Dependent Conformations and Dynamics of the Serotonin 5-HT2A Receptor Determine Its Activation and Membrane-Driven Oligomerization Properties journal, April 2012

Cholesterol Modulates the Membrane Effects and Spatial Organization of Membrane-Penetrating Ligands for G-Protein Coupled Receptors journal, September 2010

Channelrhodopsin-2 and optical control of excitable cells journal, September 2006

Structural insights into ion conduction by channelrhodopsin 2 journal, November 2017

Spectral Characteristics of the Photocycle of Channelrhodopsin-2 and Its Implication for Channel Function journal, January 2008

The cost of living in the membrane: A case study of hydrophobic mismatch for the multi-segment protein LeuT journal, April 2013

Mechanism divergence in microbial rhodopsins journal, May 2014

Quantitative Modeling of Membrane Deformations by Multihelical Membrane Proteins: Application to G-Protein Coupled Receptors journal, November 2011

Crystal structure of the channelrhodopsin light-gated cation channel journal, January 2012

In Vivo Light-Induced Activation of Neural Circuitry in Transgenic Mice Expressing Channelrhodopsin-2 journal, April 2007

Characterization of Engineered Channelrhodopsin Variants with Improved Properties and Kinetics journal, March 2009

Deformation free energy of bilayer membrane and its effect on gramicidin channel lifetime journal, December 1986

Transmembrane Domain Three Contributes to the Ion Conductance Pathway of Channelrhodopsin-2 journal, March 2013

Structural differences between the closed and open states of channelrhodopsin-2 as observed by EPR spectroscopy journal, September 2013

A mechanistic role of Helix 8 in GPCRs: Computational modeling of the dopamine D2 receptor interaction with the GIPC1–PDZ-domain journal, April 2015

Multiple Photocycles of Channelrhodopsin journal, December 2005

Curvature and Hydrophobic Forces Drive Oligomerization and Modulate Activity of Rhodopsin in Membranes journal, December 2006

Lipid composition of subcellular membranes from larvae and prepupae ofDrosophila melanogaster journal, December 1992

Interplay of G Protein-Coupled Receptors with the Membrane: Insights from Supra-Atomic Coarse Grain Molecular Dynamics Simulations journal, June 2016

Positioning and Stabilization of Dynorphin Peptides in Membrane Bilayers: the Mechanistic Role of Aromatic and Basic Residues Revealed from Comparative MD Simulations journal, January 2002

The double cubic lattice method: Efficient approaches to numerical integration of surface area and volume and to dot surface contouring of molecular assemblies journal, March 1995

A Functional Selectivity Mechanism at the Serotonin-2A GPCR Involves Ligand-Dependent Conformations of Intracellular Loop 2 journal, October 2014

Conformational Changes of Channelrhodopsin-2 journal, June 2009

Light-Induced Helix Movements in Channelrhodopsin-2 journal, January 2015

Channelrhodopsin-2, a directly light-gated cation-selective membrane channel journal, November 2003

Membrane Driven Spatial Organization of GPCRs journal, October 2013

Adjacent channelrhodopsin-2 residues within transmembranes 2 and 7 regulate cation selectivity and distribution of the two open states journal, March 2017

Early Formation of the Ion-Conducting Pore in Channelrhodopsin-2 journal, December 2014

Neurotransmitter/sodium symporter orthologue LeuT has a single high-affinity substrate site journal, December 2010

Light-Induced Movement of the Transmembrane Helix B in Channelrhodopsin-2 journal, July 2013

Not Just an Oil Slick: How the Energetics of Protein-Membrane Interactions Impacts the Function and Organization of Transmembrane Proteins journal, June 2014

Large Deformation of Helix F during the Photoreaction Cycle of Pharaonis Halorhodopsin in Complex with Azide journal, January 2013

Control of neural synchrony using channelrhodopsin-2: a computational study journal, December 2010

Intrahelical hydrogen bonding of serine, threonine and cysteine residues within α-helices and its relevance to membrane-bound proteins journal, May 1984

Two Open States with Progressive Proton Selectivities in the Branched Channelrhodopsin-2 Photocycle
journal, March 2010

Functional mechanisms of neurotransmitter transporters regulated by lipid–protein interactions of their terminal loops
journal, September 2015

Computational Optogenetics: Empirically-Derived Voltage- and Light-Sensitive Channelrhodopsin-2 Model
journal, September 2013

Channelrhodopsin-1: A Light-Gated Proton Channel in Green Algae
journal, June 2002

Temporal evolution of helix hydration in a light-gated ion channel correlates with ion conductance
journal, October 2015

Millisecond-timescale, genetically targeted optical control of neural activity
journal, August 2005

The Sixth Transmembrane Segment Is a Major Gating Component of the TMEM16A Calcium-Activated Chloride Channel
journal, March 2018

Re-Introduction of Transmembrane Serine Residues Reduce the Minimum Pore Diameter of Channelrhodopsin-2
journal, November 2012

Spontaneous Inward Opening of the Dopamine Transporter Is Triggered by PIP ₂ -Regulated Dynamics of the N-Terminus
journal, August 2015

Time-Resolved Detection of Transient Movement of Helices F and G in Doubly Spin-Labeled Bacteriorhodopsin
journal, June 2001

A GIPC1-Palmitate Switch Modulates Dopamine Drd3 Receptor Trafficking and Signaling
journal, January 2016

Role of Annular Lipids in the Functional Properties of Leucine Transporter LeuT Proteomicelles
journal, February 2016

A Usual G-Protein-Coupled Receptor in Unusual Membranes
journal, December 2015

How structural elements evolving from bacterial to human SLC6 transporters enabled new functional properties
journal, March 2018

Molecular Dynamics of Channelrhodopsin at the Early Stages of Channel Opening
journal, June 2015

Free-energy determinants of alpha-helix insertion into lipid bilayers
journal, April 1996

Photocycles of Channelrhodopsin-2
journal, January 2009

Cysteine Substitution and Labeling Provide Insight into Channelrhodopsin-2 Ion Conductance
journal, September 2015

The Preference of Tryptophan for Membrane Interfaces ^†
journal, October 1998

Energetics of Inclusion-Induced Bilayer Deformations
journal, April 1998

Laser-evoked synaptic transmission in cultured hippocampal neurons expressing channelrhodopsin-2 delivered by adeno-associated virus
journal, October 2009

Computational modeling of the N-terminus of the human dopamine transporter and its interaction with PIP ₂ -containing membranes : Modeling of DAT N-Terminus/PIP
journal, March 2015

Differential modification of the phospholipid profile by transient ischemia in rat hippocampal CA1 and CA3 regions
journal, April 2013

The lipid composition of isolated brain cells and axons
journal, January 1975

Phosphatidylinositol 4,5-bisphosphate, cholesterol, and fatty acids modulate the calcium-activated chloride channel TMEM16A (ANO1)
journal, March 2018

Bi-stable neural state switches
journal, December 2008

Escape Behavior Elicited by Single, Channelrhodopsin-2-Evoked Spikes in Zebrafish Somatosensory Neurons
journal, August 2008

Optogenetic control of heart muscle in vitro and in vivo
journal, October 2010

Modeling and Engineering aspects of ChannelRhodopsin2 System for Neural Photostimulation
conference, August 2006

Ligand-Dependent Conformations and Dynamics of the Serotonin 5-HT2A Receptor Determine Its Activation and Membrane-Driven Oligomerization Properties
journal, April 2012

Cholesterol Modulates the Membrane Effects and Spatial Organization of Membrane-Penetrating Ligands for G-Protein Coupled Receptors
journal, September 2010

Channelrhodopsin-2 and optical control of excitable cells
journal, September 2006

Structural insights into ion conduction by channelrhodopsin 2
journal, November 2017

Spectral Characteristics of the Photocycle of Channelrhodopsin-2 and Its Implication for Channel Function
journal, January 2008

The cost of living in the membrane: A case study of hydrophobic mismatch for the multi-segment protein LeuT
journal, April 2013

Mechanism divergence in microbial rhodopsins
journal, May 2014

Quantitative Modeling of Membrane Deformations by Multihelical Membrane Proteins: Application to G-Protein Coupled Receptors
journal, November 2011

Crystal structure of the channelrhodopsin light-gated cation channel
journal, January 2012

In Vivo Light-Induced Activation of Neural Circuitry in Transgenic Mice Expressing Channelrhodopsin-2
journal, April 2007

Characterization of Engineered Channelrhodopsin Variants with Improved Properties and Kinetics
journal, March 2009

Deformation free energy of bilayer membrane and its effect on gramicidin channel lifetime
journal, December 1986

Transmembrane Domain Three Contributes to the Ion Conductance Pathway of Channelrhodopsin-2
journal, March 2013

Structural differences between the closed and open states of channelrhodopsin-2 as observed by EPR spectroscopy
journal, September 2013

A mechanistic role of Helix 8 in GPCRs: Computational modeling of the dopamine D2 receptor interaction with the GIPC1–PDZ-domain
journal, April 2015

Multiple Photocycles of Channelrhodopsin
journal, December 2005

Curvature and Hydrophobic Forces Drive Oligomerization and Modulate Activity of Rhodopsin in Membranes
journal, December 2006

Lipid composition of subcellular membranes from larvae and prepupae ofDrosophila melanogaster
journal, December 1992

Interplay of G Protein-Coupled Receptors with the Membrane: Insights from Supra-Atomic Coarse Grain Molecular Dynamics Simulations
journal, June 2016

Positioning and Stabilization of Dynorphin Peptides in Membrane Bilayers: the Mechanistic Role of Aromatic and Basic Residues Revealed from Comparative MD Simulations
journal, January 2002

The double cubic lattice method: Efficient approaches to numerical integration of surface area and volume and to dot surface contouring of molecular assemblies
journal, March 1995

A Functional Selectivity Mechanism at the Serotonin-2A GPCR Involves Ligand-Dependent Conformations of Intracellular Loop 2
journal, October 2014

Conformational Changes of Channelrhodopsin-2
journal, June 2009

Light-Induced Helix Movements in Channelrhodopsin-2
journal, January 2015

Channelrhodopsin-2, a directly light-gated cation-selective membrane channel
journal, November 2003

Membrane Driven Spatial Organization of GPCRs
journal, October 2013

Adjacent channelrhodopsin-2 residues within transmembranes 2 and 7 regulate cation selectivity and distribution of the two open states
journal, March 2017

Early Formation of the Ion-Conducting Pore in Channelrhodopsin-2
journal, December 2014

Neurotransmitter/sodium symporter orthologue LeuT has a single high-affinity substrate site
journal, December 2010

Light-Induced Movement of the Transmembrane Helix B in Channelrhodopsin-2
journal, July 2013

Not Just an Oil Slick: How the Energetics of Protein-Membrane Interactions Impacts the Function and Organization of Transmembrane Proteins
journal, June 2014

Large Deformation of Helix F during the Photoreaction Cycle of Pharaonis Halorhodopsin in Complex with Azide
journal, January 2013

Control of neural synchrony using channelrhodopsin-2: a computational study
journal, December 2010

Intrahelical hydrogen bonding of serine, threonine and cysteine residues within α-helices and its relevance to membrane-bound proteins
journal, May 1984