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Coarse grained molecular dynamic simulation of mammalian mechanosensitive ion channel TRPV2

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Coarse grained molecular dynamic simulation of mammalian mechanosensitive ion channel TRPV2

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Molecular dynamics simulation is a powerful biophysical tool to gain theoretical insights into protein action. In mechanobiology, conformational change of bacterial mechanosensitive ion channels has been studied extensively. Here we studied transient receptor potential cation channel subfamily V member 2 (TRPV2), a mammalian mechanosensitive ion channel, using coarse grained molecular dynamics simulation. Coarse grained geometry of TRPV2 was generated based on a full atomic cryo-electron microscopy structure (PDB ID: 5HI9). The TRPV2 protein was embedded in a membrane composed of POPC/POPS phospholipid bilayer and solvated. The structure of TRPV2 homotetramer was stable during 1 μs simulation period. While a bacterial mechanosensitive channel MscS showed significant increase in pore radius in response to membrane tension, TRPV2 did not, as suggested by previous experimental studies. Transmembrane helix tilt, which was observed in mechanosensitive opening of MscS, was not observed in TRPV2 in membrane tension. This result suggests that mechanosensitive alteration of TRPV2 structure requires external force other than the membrane tension.

Molecular dynamics simulation is a powerful biophysical tool to gain theoretical insights into protein action. In mechanobiology, conformational change of bacterial mechanosensitive ion channels has been studied extensively. Here we studied transient receptor potential cation channel subfamily V member 2 (TRPV2), a mammalian mechanosensitive ion channel, using coarse grained molecular dynamics simulation. Coarse grained geometry of TRPV2 was generated based on a full atomic cryo-electron microscopy structure (PDB ID: 5HI9). The TRPV2 protein was embedded in a membrane composed of POPC/POPS phospholipid bilayer and solvated. The structure of TRPV2 homotetramer was stable during 1 μs simulation period. While a bacterial mechanosensitive channel MscS showed significant increase in pore radius in response to membrane tension, TRPV2 did not, as suggested by previous experimental studies. Transmembrane helix tilt, which was observed in mechanosensitive opening of MscS, was not observed in TRPV2 in membrane tension. This result suggests that mechanosensitive alteration of TRPV2 structure requires external force other than the membrane tension.

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Coarse grained molecular dynamic simulation of mammalian mechanosensitive ion channel TRPV2

  1. 1. Coarse grained molecular dynamic simulation of mammalian mechanosensitive ion channel TRPV2 Ken Takahashi, Keiji Naruse Department of Cardiovascular Physiology Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama University ISMB 2017, Singapore, Dec 14
  2. 2. Molecular dynamics (MD) simulation MscL MscS   )cos(1)(V )cos()cos( 2 1 )(V )( 2 1 )(V 4 )(V 4)(V dddihedral 2 aaangle 2 bbbond 0 el 612 Jones-Lennard                                    ijklijkl ijkijk ijij ijrel ji ij ij ij ij ij ijij nK K ddKd r qq r rr r Potential energy functions:
  3. 3. Coarse-grained molecular dynamics (CGMD) Marrink, J Phys Chem B, 2007Acetylcholine receptor All atom Coarse-grained
  4. 4. CGMD mimics nature Monticelli, JCTC, 2008 Marrink, J Phys Chem B, 2004
  5. 5. TRPV2 channel TRPV2 senses: 1. Heat 2. Mechanical stimulus 3. Lipid Romero-Romero, Proteins, 2017 Organ Cells Function Related disease Brain Neuron, astrocyte Synaptic and glial transmission Depression DRG Neuron Axon outgrowth --- DRG Neuron Nociception Pain Heart Myocyte Myocardial conduction Cardiac hypertrophy Pancreas β-Cells Insulin secretion Diabetes Intestine Myenteric neuron Intestinal motility Irritable bowel syndrome Spleen Macrophage, mast cell, lymphocyte Immune response Immunodeficiency Urinary bladder Epithelial cell Sensing stretch Bladder cancer Prostate Epithelial cell LPC receptor Prostate cancer Bone Osteoclast Calcium oscillation Cancer Muscle Skeletal and cardiac muscle cells Sensing stretch Muscular dystrophy Blood vessel Smooth muscle, endothelial cell Blood pressure control Cardiomyopathy Shibasaki, J Physiol Sci, 2016
  6. 6. TRPV2 structure PDB ID: 5HI9
  7. 7. TRPV2 structure S1 S2 S3 S4 S5S6 pore helix
  8. 8. PDB ID: 5HI9 TRPV2 structure
  9. 9. Molecule Quantity TRPV2 1 POPC 936 POPS 927 Water (CG) 97,282 Sodium 955 Simulation model GROMACS Martini CG forcefield
  10. 10. Membrane stretch Bilayer tension: -71.5 dyn/cm Duration: 4,000 ns
  11. 11. Minimum pore radius 0 1 2 3 4 5 6 7 0 500 1000 1500 2000 2500 3000 3500 4000 minimumporeradius(Å) time (ns) 0 1 2 3 4 5 6 7 0 500 1000 1500 2000 minimumporeradius(Å) time (ns) MscS TRPV2
  12. 12. Helix tilt 0 10 20 30 40 50 60 70 0 500 1000 1500 2000 2500 3000 3500 4000 helixtiltangle(degree) time (ns) s1 s2 s3 s4 s5 s6 0 10 20 30 40 50 60 70 0 500 1000 1500 2000 helixtiltangle(degree) time (ns) TM1 TM2 TM3MscS TRPV2
  13. 13. Interaction energy POPC POPS S1 S2 S3 S4 S5 PORE S6 POPC POPS S1 S2 S3 S4 S5 PORE S6Total energies LJ-SR energies Coulomb-SR energies POPS POPC POPC POPS S1 S2 S3 S4 S5 PORE S6 POPC POPS S1 S2 S3 S4 S5 PORE S6
  14. 14. Conclusion 1. TRPV2 transmembrane helices were stable against lipid bilayer tension. 2. Pore radius of TRPV2 channel did not increase in response to lipid bilayer tension. 3. Interactions between helices/lipids may determine the mechanosensitive behavior of TRPV2 channel.
  15. 15. Acknowledgment Nagoya University Yuichiro Imaichi Tatsuro Yokoyama Okayama University Kensaku Toda Kazuya Saruwatari Yutaka Kuriyama Keiji Naruse This study was supported by Grant-in-Aid for Scientific Research on Innovative Areas, No. 15H05936.

Editor's Notes

  • MODELLER is used for homology or comparative modeling of protein three-dimensional structures (1,2). The user provides an alignment of a sequence to be modeled with known related structures and MODELLER automatically calculates a model containing all non-hydrogen atoms. MODELLER implements comparative protein structure modeling by satisfaction of spatial restraints (3,4), and can perform many additional tasks, including de novo modeling of loops in protein structures, optimization of various models of protein structure with respect to a flexibly defined objective function, multiple alignment of protein sequences and/or structures, clustering, searching of sequence databases, comparison of protein structures, etc. MODELLER is available for download for most Unix/Linux systems, Windows, and Mac.
    Modeller was developed by UCSF.

    PDB ID: 5HI9
    homotetramer
  • MODELLER is used for homology or comparative modeling of protein three-dimensional structures (1,2). The user provides an alignment of a sequence to be modeled with known related structures and MODELLER automatically calculates a model containing all non-hydrogen atoms. MODELLER implements comparative protein structure modeling by satisfaction of spatial restraints (3,4), and can perform many additional tasks, including de novo modeling of loops in protein structures, optimization of various models of protein structure with respect to a flexibly defined objective function, multiple alignment of protein sequences and/or structures, clustering, searching of sequence databases, comparison of protein structures, etc. MODELLER is available for download for most Unix/Linux systems, Windows, and Mac.
    Modeller was developed by UCSF.
  • POPC 936
    POPS 927
    Water 97282
    Sodium 955
  • 3.6–3.8-Å-radius sphere for pottasium

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