The allosteric mechanism of substrate-specific transport in SLC6 is mediated by a volumetric sensor

LeVine, Michael V.; Terry, Daniel S.; Khelashvili, George; Siegel, Zarek S.; Quick, Matthias; Javitch, Jonathan A.; Blanchard, Scott C.; Weinstein, Harel

doi:10.1073/pnas.1903020116

Title: The allosteric mechanism of substrate-specific transport in SLC6 is mediated by a volumetric sensor

Abstract

Neurotransmitter:sodium symporters (NSSs) in the SLC6 family terminate neurotransmission by coupling the thermodynamically favorable transport of ions to the thermodynamically unfavorable transport of neurotransmitter back into presynaptic neurons. Results from many structural, functional, and computational studies on LeuT, a bacterial NSS homolog, have provided critical insight into the mechanism of sodium-coupled transport, but the mechanism underlying substrate-specific transport rates is still not understood. We present a combination of molecular dynamics simulations, single-molecule fluorescence resonance energy transfer (smFRET) imaging, and measurements of Na⁺ binding and substrate transport that reveals an allosteric substrate specificity mechanism. In this mechanism, residues F259 and I359 in the substrate binding pocket couple the binding of substrate to Na⁺ release from the Na2 site by allosterically modulating the stability of a partially open, inward-facing state. We propose a model for transport selectivity in which residues F259 and I359 act as a volumetric sensor that inhibits the transport of bulky amino acids.

Authors:

LeVine, Michael V. ^[1]; Terry, Daniel S. ^[1]; Khelashvili, George ^[1]; Siegel, Zarek S. ^[1]; Quick, Matthias ^[2]; Javitch, Jonathan A. ^[2];

^[1];

^[1]

Weill Cornell Medicine, New York, NY (United States)
Columbia Univ., New York, NY (United States); New York State Psychiatric Inst. New York, NY (United States)

Publication Date:: 2019-07-19

Research Org.:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC) (OLCF); Univ. of California, Oakland, CA (United States); UT-Battelle LLC/ORNL, Oak Ridge, TN (United States)

Sponsoring Org.:: USDOE Office of Science (SC), Advanced Scientific Computing Research (ASCR); National Institutes of Health (NIH); National Science Foundation (NSF)

OSTI Identifier:: 1565765

Grant/Contract Number:: AC02-05CH11231; AC05-00OR22725; R21-MH099491; U54-GM087510; P01-DA012408; R01-DA041510; F31-DA035533; ACI-1053575; R01-GM116961

Resource Type:: Accepted Manuscript

Journal Name:: Proceedings of the National Academy of Sciences of the United States of America

Additional Journal Information:: Journal Volume: 116; Journal Issue: 32; Journal ID: ISSN 0027-8424

Publisher:: National Academy of Sciences

Country of Publication:: United States

Language:: English

Subject:: 60 APPLIED LIFE SCIENCES

Citation Formats


                    LeVine, Michael V., Terry, Daniel S., Khelashvili, George, Siegel, Zarek S., Quick, Matthias, Javitch, Jonathan A., Blanchard, Scott C., and Weinstein, Harel. The allosteric mechanism of substrate-specific transport in SLC6 is mediated by a volumetric sensor.  United States: N. p., 2019. 
        Web.  doi:10.1073/pnas.1903020116.

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                    LeVine, Michael V., Terry, Daniel S., Khelashvili, George, Siegel, Zarek S., Quick, Matthias, Javitch, Jonathan A., Blanchard, Scott C., & Weinstein, Harel. The allosteric mechanism of substrate-specific transport in SLC6 is mediated by a volumetric sensor.  United States.  doi:https://doi.org/10.1073/pnas.1903020116

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                    LeVine, Michael V., Terry, Daniel S., Khelashvili, George, Siegel, Zarek S., Quick, Matthias, Javitch, Jonathan A., Blanchard, Scott C., and Weinstein, Harel. Fri .  
        "The allosteric mechanism of substrate-specific transport in SLC6 is mediated by a volumetric sensor".  United States.  doi:https://doi.org/10.1073/pnas.1903020116.  https://www.osti.gov/servlets/purl/1565765.

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@article{osti_1565765,

  title        = {The allosteric mechanism of substrate-specific transport in SLC6 is mediated by a volumetric sensor},

  author       = {LeVine, Michael V. and Terry, Daniel S. and Khelashvili, George and Siegel, Zarek S. and Quick, Matthias and Javitch, Jonathan A. and Blanchard, Scott C. and Weinstein, Harel},

  abstractNote = {Neurotransmitter:sodium symporters (NSSs) in the SLC6 family terminate neurotransmission by coupling the thermodynamically favorable transport of ions to the thermodynamically unfavorable transport of neurotransmitter back into presynaptic neurons. Results from many structural, functional, and computational studies on LeuT, a bacterial NSS homolog, have provided critical insight into the mechanism of sodium-coupled transport, but the mechanism underlying substrate-specific transport rates is still not understood. We present a combination of molecular dynamics simulations, single-molecule fluorescence resonance energy transfer (smFRET) imaging, and measurements of Na+ binding and substrate transport that reveals an allosteric substrate specificity mechanism. In this mechanism, residues F259 and I359 in the substrate binding pocket couple the binding of substrate to Na+ release from the Na2 site by allosterically modulating the stability of a partially open, inward-facing state. We propose a model for transport selectivity in which residues F259 and I359 act as a volumetric sensor that inhibits the transport of bulky amino acids.},

  doi          = {10.1073/pnas.1903020116},

  journal      = {Proceedings of the National Academy of Sciences of the United States of America},

  number       = 32,

  volume       = 116,

  place        = {United States},

  year         = {2019},

  month        = {7}

}

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DOI: https://doi.org/10.1073/pnas.1903020116

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Works referencing / citing this record:

Comparative Protein Structure Modeling Using MODELLER
journal, November 2007

Eswar, Narayanan; Webb, Ben; Marti-Renom, Marc A.
Current Protocols in Protein Science, Vol. 50, Issue 1
DOI: 10.1002/0471140864.ps0209s50

Scalable molecular dynamics with NAMD
journal, January 2005

Phillips, James C.; Braun, Rosemary; Wang, Wei
Journal of Computational Chemistry, Vol. 26, Issue 16, p. 1781-1802
DOI: 10.1002/jcc.20289

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journal, March 1993

Schrauber, Hannelore; Eisenhaber, Frank; Argos, Patrick
Journal of Molecular Biology, Vol. 230, Issue 2
DOI: 10.1006/jmbi.1993.1172

A rapid, sensitive, and specific method for the determination of protein in dilute solution
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Schaffner, W.; Weissmann, C.
Analytical Biochemistry, Vol. 56, Issue 2
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Humphrey, William; Dalke, Andrew; Schulten, Klaus
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Computational approaches to detect allosteric pathways in transmembrane molecular machines
journal, July 2016

Stolzenberg, Sebastian; Michino, Mayako; LeVine, Michael V.
Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1858, Issue 7
DOI: 10.1016/j.bbamem.2016.01.010

Ion-Controlled Conformational Dynamics in the Outward-Open Transition from an Occluded State of LeuT
journal, September 2012

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Neurotransmitter:sodium symporters (NSSs) terminate neurotransmission by Na⁺-dependent reuptake of released neurotransmitters. Previous studies suggested that Na⁺-binding reconfigures dynamically coupled structural elements in an allosteric interaction network (AIN) responsible for function-related conformational changes, but the intramolecular pathway of this mechanism has remained uncharted. Here we describe a new approach for the modeling and analysis of intramolecular dynamics in the bacterial NSS homolog LeuT. From microsecond-scale molecular dynamics simulations and cognate experimental verifications in both LeuT and human dopamine transporter (hDAT), we apply the novel method to identify the composition and the dynamic properties of their conserved AIN. In LeuT, two differentmore »« less
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Abstract

Citation Formats

Thermodynamic Coupling Function Analysis of Allosteric Mechanisms in the Human Dopamine Transporter journal, January 2018

X-ray structures of LeuT in substrate-free outward-open and apo inward-open states journal, January 2012

Ultra-stable organic fluorophores for single-molecule research journal, January 2014

Simple Allosteric Model for Membrane Pumps journal, August 1966

AIM for Allostery: Using the Ising Model to Understand Information Processing and Transmission in Allosteric Biomolecular Systems journal, May 2015

Scalable molecular dynamics with NAMD journal, January 2005

Molecular Determinants for Substrate Interactions with the Glycine Transporter GlyT2 journal, November 2017

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

Glu-311 in External Loop 4 of the Sodium/Proline Transporter PutP Is Crucial for External Gate Closure journal, January 2016

The Allostery Landscape: Quantifying Thermodynamic Couplings in Biomolecular Systems journal, November 2016

Computational approaches to detect allosteric pathways in transmembrane molecular machines journal, July 2016

The role of transmembrane segment 5 (TM5) in Na2 release and the conformational transition of neurotransmitter:sodium symporters toward the inward-open state journal, March 2017

Chloride binding site of neurotransmitter sodium symporters journal, May 2013

High-Affinity Adaptors for Switchable Recognition of Histidine-Tagged Proteins journal, July 2005

Allosteric modulation of human dopamine transporter activity under conditions promoting its dimerization journal, June 2017

Unlocking the molecular secrets of sodium-coupled transporters journal, May 2009

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

Single-molecule imaging of non-equilibrium molecular ensembles on the millisecond timescale journal, February 2016

Neurotransmitter transporters as molecular targets for addictive drugs journal, June 1998

Unbiased Simulations Reveal the Inward-Facing Conformation of the Human Serotonin Transporter and Na+ Ion Release journal, October 2011

Conformational transitions of the sodium-dependent sugar transporter, vSGLT journal, March 2018

The bright future of single-molecule fluorescence imaging journal, June 2014

Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters journal, July 2005

Ion-Controlled Conformational Dynamics in the Outward-Open Transition from an Occluded State of LeuT journal, September 2012

X-ray structures of Drosophila dopamine transporter in complex with nisoxetine and reboxetine journal, May 2015

A Competitive Inhibitor Traps LeuT in an Open-to-Out Conformation journal, December 2008

Rotamers: To be or not to be? journal, March 1993

Common Folds and Transport Mechanisms of Secondary Active Transporters journal, May 2013

Substrate-induced Unlocking of the Inner Gate Determines the Catalytic Efficiency of a Neurotransmitter:Sodium Symporter journal, September 2015

Neurotransmitter and psychostimulant recognition by the dopamine transporter journal, May 2015

The LeuT-fold neurotransmitter:sodium symporter MhsT has two substrate sites journal, August 2018

Conformational dynamics of ligand-dependent alternating access in LeuT journal, April 2014

Detection of allosteric signal transmission by information-theoretic analysis of protein dynamics journal, February 2012

A Simple Method for Automated Equilibration Detection in Molecular Simulations journal, March 2016

Update of the CHARMM All-Atom Additive Force Field for Lipids: Validation on Six Lipid Types journal, June 2010

Allosteric Mechanisms of Molecular Machines at the Membrane: Transport by Sodium-Coupled Symporters journal, February 2016

Mechanism of chloride interaction with neurotransmitter:sodium symporters journal, August 2007

The Mechanism of a Neurotransmitter:Sodium Symporter—Inward Release of Na+ and Substrate Is Triggered by Substrate in a Second Binding Site journal, June 2008

Density‐functional thermochemistry. III. The role of exact exchange journal, April 1993

Structural basis for recognition of diverse antidepressants by the human serotonin transporter journal, January 2018

A rapid, sensitive, and specific method for the determination of protein in dilute solution journal, December 1973

Computational modeling with forward and reverse engineering links signaling network and genomic regulatory responses: NF-κB signaling-induced gene expression responses in inflammation journal, January 2010

X-ray structure of dopamine transporter elucidates antidepressant mechanism journal, September 2013

Computational characterization of structural dynamics underlying function in active membrane transporters journal, April 2015

Two Na + Sites Control Conformational Change in a Neurotransmitter Transporter Homolog journal, November 2015

Identification of a Second Substrate-binding Site in Solute-Sodium Symporters journal, November 2014

A partially-open inward-facing intermediate conformation of LeuT is associated with Na+ release and substrate transport journal, January 2018

Accurate and efficient integration for molecular dynamics simulations at constant temperature and pressure journal, October 2013

Transport domain unlocking sets the uptake rate of an aspartate transporter journal, February 2015

Coupled Global and Local Changes Direct Substrate Translocation by Neurotransmitter-Sodium Symporter Ortholog LeuT journal, August 2013

Conformational cycle and ion-coupling mechanism of the Na+/hydantoin transporter Mhp1 journal, September 2014

Optimization of the Additive CHARMM All-Atom Protein Force Field Targeting Improved Sampling of the Backbone ϕ, ψ and Side-Chain χ 1 and χ 2 Dihedral Angles journal, August 2012

Computation-guided analysis of paroxetine binding to hSERT reveals functionally important structural elements and dynamics journal, December 2019

X-ray structures and mechanism of the human serotonin transporter journal, April 2016

Substrate-modulated gating dynamics in a Na+-coupled neurotransmitter transporter homologue journal, April 2011

Single-molecule dynamics of gating in a neurotransmitter transporter homologue journal, May 2010

CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations Using the CHARMM36 Additive Force Field journal, December 2015

NbIT - A New Information Theory-Based Analysis of Allosteric Mechanisms Reveals Residues that Underlie Function in the Leucine Transporter LeuT journal, May 2014

Restoration of Single-Channel Currents Using the Segmental k-Means Method Based on Hidden Markov Modeling journal, March 2004

Monitoring the function of membrane transport proteins in detergent-solubilized form journal, February 2007

Conformational dynamics of a neurotransmitter:sodium symporter in a lipid bilayer journal, February 2017

Comparative Protein Structure Modeling Using MODELLER journal, November 2007

A Comprehensive Structure-Based Alignment of Prokaryotic and Eukaryotic Neurotransmitter/Na + Symporters (NSS) Aids in the Use of the LeuT Structure to Probe NSS Structure and Function journal, July 2006

State-dependent Conformations of the Translocation Pathway in the Tyrosine Transporter Tyt1, a Novel Neurotransmitter:Sodium Symporter from Fusobacterium nucleatum journal, June 2006

Canonical dynamics: Equilibrium phase-space distributions journal, March 1985

Dynamical networks in tRNA:protein complexes journal, April 2009

A smooth particle mesh Ewald method journal, November 1995

An Intracellular Interaction Network Regulates Conformational Transitions in the Dopamine Transporter journal, April 2008

Residues crucial for maintaining short paths in network communication mediate signaling in proteins journal, January 2006

Ab Initio Calculation of Vibrational Absorption and Circular Dichroism Spectra Using Density Functional Force Fields journal, November 1994

Neurotransmitter transporters and their impact on the development of psychopharmacology: Neurotransmitter transporters journal, January 2006

The Role of Local Hydration and Hydrogen-Bonding Dynamics in Ion and Solute Release from Ion-Coupled Secondary Transporters journal, March 2011

VMD: Visual molecular dynamics journal, February 1996

A Markov State-based Quantitative Kinetic Model of Sodium Release from the Dopamine Transporter journal, January 2017

Substrate-dependent proton antiport in neurotransmitter:sodium symporters journal, December 2009

Anton, a special-purpose machine for molecular dynamics simulation journal, July 2008

Anton, a special-purpose machine for molecular dynamics simulation conference, January 2007

Thermodynamic Coupling Function Analysis of Allosteric Mechanisms in the Human Dopamine Transporter
journal, January 2018

X-ray structures of LeuT in substrate-free outward-open and apo inward-open states
journal, January 2012

Ultra-stable organic fluorophores for single-molecule research
journal, January 2014

Simple Allosteric Model for Membrane Pumps
journal, August 1966

AIM for Allostery: Using the Ising Model to Understand Information Processing and Transmission in Allosteric Biomolecular Systems
journal, May 2015

Scalable molecular dynamics with NAMD
journal, January 2005

Molecular Determinants for Substrate Interactions with the Glycine Transporter GlyT2
journal, November 2017

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

Glu-311 in External Loop 4 of the Sodium/Proline Transporter PutP Is Crucial for External Gate Closure
journal, January 2016

The Allostery Landscape: Quantifying Thermodynamic Couplings in Biomolecular Systems
journal, November 2016

Computational approaches to detect allosteric pathways in transmembrane molecular machines
journal, July 2016

The role of transmembrane segment 5 (TM5) in Na2 release and the conformational transition of neurotransmitter:sodium symporters toward the inward-open state
journal, March 2017

Chloride binding site of neurotransmitter sodium symporters
journal, May 2013

High-Affinity Adaptors for Switchable Recognition of Histidine-Tagged Proteins
journal, July 2005

Allosteric modulation of human dopamine transporter activity under conditions promoting its dimerization
journal, June 2017

Unlocking the molecular secrets of sodium-coupled transporters
journal, May 2009

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

Single-molecule imaging of non-equilibrium molecular ensembles on the millisecond timescale
journal, February 2016

Neurotransmitter transporters as molecular targets for addictive drugs
journal, June 1998

Unbiased Simulations Reveal the Inward-Facing Conformation of the Human Serotonin Transporter and Na+ Ion Release
journal, October 2011

Conformational transitions of the sodium-dependent sugar transporter, vSGLT
journal, March 2018

The bright future of single-molecule fluorescence imaging
journal, June 2014

Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters
journal, July 2005

Ion-Controlled Conformational Dynamics in the Outward-Open Transition from an Occluded State of LeuT
journal, September 2012

X-ray structures of Drosophila dopamine transporter in complex with nisoxetine and reboxetine
journal, May 2015

A Competitive Inhibitor Traps LeuT in an Open-to-Out Conformation
journal, December 2008

Rotamers: To be or not to be?
journal, March 1993

Common Folds and Transport Mechanisms of Secondary Active Transporters
journal, May 2013

Substrate-induced Unlocking of the Inner Gate Determines the Catalytic Efficiency of a Neurotransmitter:Sodium Symporter
journal, September 2015

Neurotransmitter and psychostimulant recognition by the dopamine transporter
journal, May 2015

The LeuT-fold neurotransmitter:sodium symporter MhsT has two substrate sites
journal, August 2018

Conformational dynamics of ligand-dependent alternating access in LeuT
journal, April 2014

Detection of allosteric signal transmission by information-theoretic analysis of protein dynamics
journal, February 2012

A Simple Method for Automated Equilibration Detection in Molecular Simulations
journal, March 2016

Update of the CHARMM All-Atom Additive Force Field for Lipids: Validation on Six Lipid Types
journal, June 2010

Allosteric Mechanisms of Molecular Machines at the Membrane: Transport by Sodium-Coupled Symporters
journal, February 2016

Mechanism of chloride interaction with neurotransmitter:sodium symporters
journal, August 2007

The Mechanism of a Neurotransmitter:Sodium Symporter—Inward Release of Na+ and Substrate Is Triggered by Substrate in a Second Binding Site
journal, June 2008

Density‐functional thermochemistry. III. The role of exact exchange
journal, April 1993

Structural basis for recognition of diverse antidepressants by the human serotonin transporter
journal, January 2018

A rapid, sensitive, and specific method for the determination of protein in dilute solution
journal, December 1973

Computational modeling with forward and reverse engineering links signaling network and genomic regulatory responses: NF-κB signaling-induced gene expression responses in inflammation
journal, January 2010

X-ray structure of dopamine transporter elucidates antidepressant mechanism
journal, September 2013

Computational characterization of structural dynamics underlying function in active membrane transporters
journal, April 2015

Two Na ⁺ Sites Control Conformational Change in a Neurotransmitter Transporter Homolog
journal, November 2015

Identification of a Second Substrate-binding Site in Solute-Sodium Symporters
journal, November 2014

A partially-open inward-facing intermediate conformation of LeuT is associated with Na+ release and substrate transport
journal, January 2018

Accurate and efficient integration for molecular dynamics simulations at constant temperature and pressure
journal, October 2013

Transport domain unlocking sets the uptake rate of an aspartate transporter
journal, February 2015

Coupled Global and Local Changes Direct Substrate Translocation by Neurotransmitter-Sodium Symporter Ortholog LeuT
journal, August 2013

Conformational cycle and ion-coupling mechanism of the Na+/hydantoin transporter Mhp1
journal, September 2014

Optimization of the Additive CHARMM All-Atom Protein Force Field Targeting Improved Sampling of the Backbone ϕ, ψ and Side-Chain χ ₁ and χ ₂ Dihedral Angles
journal, August 2012

Computation-guided analysis of paroxetine binding to hSERT reveals functionally important structural elements and dynamics
journal, December 2019

X-ray structures and mechanism of the human serotonin transporter
journal, April 2016

Substrate-modulated gating dynamics in a Na+-coupled neurotransmitter transporter homologue
journal, April 2011

Single-molecule dynamics of gating in a neurotransmitter transporter homologue
journal, May 2010

CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations Using the CHARMM36 Additive Force Field
journal, December 2015

NbIT - A New Information Theory-Based Analysis of Allosteric Mechanisms Reveals Residues that Underlie Function in the Leucine Transporter LeuT
journal, May 2014

Restoration of Single-Channel Currents Using the Segmental k-Means Method Based on Hidden Markov Modeling
journal, March 2004

Monitoring the function of membrane transport proteins in detergent-solubilized form
journal, February 2007

Conformational dynamics of a neurotransmitter:sodium symporter in a lipid bilayer
journal, February 2017

Comparative Protein Structure Modeling Using MODELLER
journal, November 2007

A Comprehensive Structure-Based Alignment of Prokaryotic and Eukaryotic Neurotransmitter/Na ⁺ Symporters (NSS) Aids in the Use of the LeuT Structure to Probe NSS Structure and Function
journal, July 2006

State-dependent Conformations of the Translocation Pathway in the Tyrosine Transporter Tyt1, a Novel Neurotransmitter:Sodium Symporter from Fusobacterium nucleatum
journal, June 2006

Canonical dynamics: Equilibrium phase-space distributions
journal, March 1985

Dynamical networks in tRNA:protein complexes
journal, April 2009

A smooth particle mesh Ewald method
journal, November 1995

An Intracellular Interaction Network Regulates Conformational Transitions in the Dopamine Transporter
journal, April 2008

Residues crucial for maintaining short paths in network communication mediate signaling in proteins
journal, January 2006

Ab Initio Calculation of Vibrational Absorption and Circular Dichroism Spectra Using Density Functional Force Fields
journal, November 1994

Neurotransmitter transporters and their impact on the development of psychopharmacology: Neurotransmitter transporters
journal, January 2006

The Role of Local Hydration and Hydrogen-Bonding Dynamics in Ion and Solute Release from Ion-Coupled Secondary Transporters
journal, March 2011

VMD: Visual molecular dynamics
journal, February 1996

A Markov State-based Quantitative Kinetic Model of Sodium Release from the Dopamine Transporter
journal, January 2017

Substrate-dependent proton antiport in neurotransmitter:sodium symporters
journal, December 2009

Anton, a special-purpose machine for molecular dynamics simulation
journal, July 2008

Anton, a special-purpose machine for molecular dynamics simulation
conference, January 2007

Spontaneous Inward Opening of the Dopamine Transporter is Triggered by PIP2-Regulated Dynamics of the N-Terminus
journal, February 2016

Comparative Protein Structure Modeling Using MODELLER
journal, November 2007

Scalable molecular dynamics with NAMD
journal, January 2005