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.
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.
Coarse-grained molecular dynamics (CGMD)
Marrink, J Phys Chem B, 2007Acetylcholine receptor
All atom
Coarse-grained

4.
CGMD mimics nature
Monticelli, JCTC, 2008
Marrink, J Phys Chem B, 2004

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.
TRPV2 structure
PDB ID: 5HI9

7.
TRPV2 structure
S1
S2
S3
S4
S5S6
pore helix

8.
PDB ID: 5HI9
TRPV2 structure

9.
Molecule Quantity
TRPV2 1
POPC 936
POPS 927
Water (CG) 97,282
Sodium 955
Simulation model
GROMACS
Martini CG forcefield

10.
Membrane stretch
Bilayer tension: -71.5 dyn/cm
Duration: 4,000 ns

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.
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.
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.
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.
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.