Focused ultrasound (FUS) has a wide range of medical applications. Nowadays, the diagnostic and therapeutic ultrasound procedures are routinely used; effects of ultrasound on biological systems at the molecular level are, however, not fully understood. Experimental results on the interaction of the cell membrane, a simplest but important system component, with ultrasound are controversial. Molecular dynamics (MD) simulations could provide valuable insights, but there is no single study on the mechanism of the FUS induced structural changes in cell membranes. With this in mind, we develop a simple method to include FUS into a standard MD simulation. Adopting the 1,2-dioleoyl-sn-glycero-3-phosphocholine lipid membrane as a representative model described by the MARTINI coarse-grained force field, and using experimental values of the ultrasound frequency and intensity, we show that the heat and bubble cavitation are not the primary direct mechanisms that cause structural changes in the membrane. The spatial pressure gradients between the focused and free regions and between the parallel and perpendicular directions to the membrane are the origin of the mechanism. These gradients force lipids to move out of the focused region, forming a lipid flow along the membrane diagonal. Lipids in the free region move in the opposite direction due to the conservation of the total momentum. These opposite motions create wrinkles along the membrane diagonal at low FUS intensities and tear up the membrane at high FUS intensities. Once the membrane is torn up, it is not easy to reform. The implication of our findings in the FUS-induced drug delivery is discussed in some detail.
REFERENCES
1.
A.
Sarvazyan
, O. V.
Rudenko
, and W. L.
Nyborg
, “Biomedical applications of radiation force of ultrasound: Historical roots and physical basis
,” Ultrasound Med. Biol.
36
, 1379
(2010
).2.
Z.
Izadifar
, P.
Babyn
, and D.
Chapman
, “Mechanical and biological effects of ultrasound: A review of present knowledge
,” Ultrasound Med. Biol.
43
, 1085
(2017
).3.
A. S.
Elhelf
, H.
Albahar
, U.
Shah
, A.
Oto
, E.
Cressman
, and M.
Almekkawy
, “High intensity focused ultrasound: The fundamentals, clinical applications and research trends
,” Diagn. Interventional Imaging
99
, 349
(2018
).4.
K.
Hynynen
, N.
McDannold
, N.
Vykhodtseva
, and F. A.
Jolesz
, “Noninvasive MR imaging-guided focal opening of the blood-brain barrier in rabbits
,” Radiology
220
, 640
(2001
).5.
N.
McDannol
, C. D.
Arvanitis
, N.
Vykhodtseva
, and M. S.
Livingstone
, “Temporary disruption of the blood-brain barrier by use of ultrasound and microbubbles: Safety and efficacy evaluation in rhesus macaques
,” Cancer Res.
72
, 3652
–3663
(2012
).6.
J.
Wu
, “Theoretical study on shear stress generated by microstreaming surrounding contrast agents attached to living cells
,” Ultrasound Med. Biol.
28
, 125
–129
(2002
).7.
J.
Wu
, J.
Ross
, and J.
Chiu
, “Reparable sonoporation generated by microstreaming
,” J. Acoust. Soc. Am.
111
, 1460
–1464
(2002
).8.
P.
Marmottant
and S.
Hilgenfeldt
, “Controlled vesicle deformation and lysis by single oscillating bubbles
,” Nature
423
, 153
–156
(2003
).9.
J.
WuShear
, “Stress in cells generated by ultrasound
,” Prog. Biophys. Mol. Biol.
93
, 363
(2007
).10.
J.
Wu
and W. L.
Nyborg
, “Ultrasound, cavitation bubbles and their interaction with cells
,” Adv. Drug Delivery Rev.
60
, 1103
(2008
).11.
S.
Lee
, T.
Anderson
, H.
Zhang
, T. J.
Flotte
, and A. G.
Doukas
, “Alteration of cell membrane by stress waves in vitro
,” Ultrasound Med. Biol.
22
, 1285
(1996
).12.
M.
Lokhandwalla
and B.
Sturtevant
, “Mechanical haemolysis in shock wave lithotripsy (SWL): I. Analysis of cell deformation due to SWL flow-fields
,” Phys. Med. Biol.
46
, 413
(2001
).13.
V. G.
Zarnitsyn
and M. R.
Prausnitz
, “Physical parameters influencing optimization of ultrasound-mediated DNA transfection
,” Ultrasound Med. Biol.
30
, 527
–538
(2004
).14.
H. Y.
Lin
and H. L.
Thomas
, “Factors affecting responsivity of unilamellar liposomes to 20 kHz ultrasound
,” Langmuir
20
, 6100
–6106
(2004
).15.
R. K.
Schlicher
, H.
Radhakrishna
, T. P.
Tolentino
, R. P.
Apkarian
, V.
Zarnitsyn
, and M. R.
Prausnitz
, “Mechanism of intracellular delivery by acoustic cavitation
,” Ultrasound Med. Biol.
32
, 915
–924
(2006
).16.
M.
Aryal
, C. D.
Arvanitis
, P. M.
Alexander
, and N.
McDannold
, “Ultrasound-mediated blood–brain barrier disruption for targeted drug delivery in the central nervous system
,” Adv. Drug. Delivery Rev.
72
, 94
–109
(2014
).17.
P.
Pohl
, Y. N.
Antonenko
, and E.
Rosenfeld
, “Effect of ultrasound on the pH profiles in the unstirred layers near planar bilayer lipid membranes measured by microelectrodes
,” Biochim. Biophys. Acta
1152
, 155
(1993
).18.
P.
Pohl
, E.
Rosenfeld
, and R.
Millner
, “Effects of ultrasound on the steady-state transmembrane pH gradient and the permeability of acetic acid through bilayer lipid membranes
,” Biochim. Biophys. Acta
1145
, 279
(1993
).19.
K. R.
Rohr
and J. A.
Rooney
, “Effect of ultrasound on a bilayer lipid membrane
,” Biophys. J.
23
, 33
(1978
).20.
M. L.
Prieto
, O.
Oralkan
, B. T.
Khuri-Yakub
, and M. C.
Maduke
, “Dynamic response of model lipid membranes to ultrasonic radiation force
,” PLoS ONE
8
, e77115
(2013
).21.
M.
Shervani-Tabar
, A. H.
Aghdam
, B.
Khoo
, V.
Farhangmehr
, and B.
Farzaneh
, “Numerical analysis of a cavitation bubble in the vicinity of an elastic membrane
,” Fluid Dyn. Res.
45
, 055503
(2013
).22.
G. C.
Ganzenmuller
, S.
Hiermaier
, and M. O.
Steinhauser
, “Shock-wave induced damage in lipid bilayers: A dissipative particle dynamics simulation study
,” Soft Matter
7
, 4307
–4317
(2011
).23.
A.
Choubey
, M.
Vedadi
, K.
Nomura
, R. K.
Kalia
, A.
Nakano
, and P.
Vashishta
, “Poration of lipid bilayers by shock-induced nanobubble collapse
,” Appl. Phys. Lett.
98
, 023701
(2011
).24.
D.
Schanz
, B.
Metten
, T.
Kurz
, and W.
Lauterborn
, “Molecular dynamics simulations of cavitation bubble collapse and sonoluminescence
,” New J. Phys.
14
, 113019
(2012
).25.
A. S. K.
Nomura
, R. K.
Kalia
, A.
Nakano
, and P.
Vashishta
, “Nanobubble collapse on a silica surface in water: Billion-atom reactive molecular dynamics simulations
,” Phys. Rev. Lett.
111
, 184503
(2013
).26.
K.
Koshiyama
, T.
Kodama
, T.
Yano
, and S.
Fujikawa
, “Structural change in lipid bilayers and water penetration induced by shock waves: Molecular dynamics simulations
,” Biophys. J.
91
, 2198
–2205
(2006
).27.
K. P.
Santo
and M. L.
Berkowitz
, “Shock wave induced collapse of arrays of nanobubbles located next to a lipid membrane: Coarse grained computer simulations
,” J. Phys. Chem. B
119
, 8879
–8889
(2014
).28.
K. P.
Santo
and M. L.
Berkowitz
, “Shock wave interaction with a phospholipid membrane: Coarse-grained computer simulations
,” J. Chem. Phys.
140
, 054906
(2014
).29.
H.
Fu
, J.
Comer
, W.
Cai
, and C.
Chipot
, “Sonoporation at small and large length scales: Effect of cavitation bubble collapse on membranes
,” J. Phys. Chem. Lett.
6
, 413
–418
(2015
).30.
K.
Koshiyama
and S.
Wada
, “Collapse of a lipid-coated nanobubble and subsequent liposome formation
,” Sci. Rep.
6
, 28164
(2016
).31.
M. H.
Viet
, P.
Derreumaux
, and P. H.
Nguyen
, “Nonequilibrium all-atom molecular dynamics simulation of the ultrasound induced bubble cavitation and application to dissociate amyloid fibril
,” J. Chem. Phys.
145
, 174113
(2016
).32.
M. H.
Viet
, M. T.
Phan
, M.
Li
, P.
Derreumaux
, W.
Junmei
, N. T.
Van-Oanh
, P.
Derreumaux
, and P. H.
Nguyen
, “Molecular mechanism of the cell membrane pore formation induced by bubble stable cavitation
,” J. Phys. Chem. B
123
, 71
(2019
).33.
M. H.
Viet
, M.
Li
, P.
Derreumaux
, and P. H.
Nguyen
, “Rayleigh-Plesset equation of the bubble stable cavitation in water: A nonequilibrium all-atom molecular dynamics simulation study
,” J. Chem. Phys.
148
, 094505
(2018
).34.
S. J.
Marrink
, J.
Risselada
, S.
Yefimov
, D. P.
Tieleman
, and A. H.
de Vries
, “The MARTINI force field: Coarse grained model for biomolecular simulations
,” J. Phys. Chem. B
111
, 7812
–7824
(2007
).35.
S. J.
Marrink
and D. P.
Tieleman
, “Perspective on the MARTINI
,” Chem. Soc. Rev.
42
, 6801
–6822
(2013
).36.
E.
Lindahl
, B.
Hess
, and D.
van der Spoel
, “GROMACS 3.0: A package for molecular simulation and trajectory analysis
,” J. Mol. Mod.
7
, 306
–317
(2001
).37.
H. J. C.
Berendsen
, J. P. M.
Postma
, W. F.
van Gunsteren
, A.
Dinola
, and J. R.
Haak
, “Molecular-dynamics with coupling to an external bath
,” J. Chem. Phys.
81
, 3684
–3690
(1984
).38.
S. A.
Quadri
, M.
Waqas
, I.
Khan
, M. A.
Khan
, S. S.
Suriya
, M.
Farooqui
, and B.
Fiani
, “High-intensity focused ultrasound: Past, present, and future in neurosurgery
,” Neurosurg. Focus
44
, E16
(2018
).39.
J. J.
Choi
, S. A.
Small
, and E. E.
Konofagou
, “Optimization of blood-brain barrier opening in mice using focused ultrasound
,” in IEEE Ultrasonics Symposium
(IEEE
, 2006
), pp. 540
–543
.40.
G. T.
Haar
, “Safety first: Progress in calibrating high-intensity focused ultrasound treatments
,” Imaging Med.
5
, 567
(2013
).41.
T.
Darden
, D.
York
, and L.
Pedersen
, “Particle mesh Ewald: An N·log(N) method for Ewald sums in large systems
,” J. Chem. Phys.
98
, 10089
–10092
(1993
).42.
S. J.
Marrink
, X.
Periole
, D. P.
Tieleman
, and A. H.
de Vries
, “Comment on: ‘On using a too large integration time step in molecular dynamics simulations of coarse-grained molecular models’ by M. Winger, D. Trzesniak, R. Baron, and W. F. van Gunsteren, Phys. Chem. Chem. Phys., 2009, 11, 1934
,” Phys. Chem. Chem. Phys.
12
, 2254
(2009
).43.
P.
Nguyen
, M. S.
Li
, J. E.
Staub
, and D.
Thirumalai
, “Monomer adds to preformed structured oligomers of Aβ-peptides by a two-stage dock-lock mechanism
,” Proc. Natl. Acad. Sci. U. S. A.
104
, 111
–116
(2007
).44.
U.
Adhikari
, A.
Goliaei
, and M. L.
Berkowitz
, “Mechanism of membrane poration by shock wave induced nanobubble collapse: A molecular study
,” J. Phys. Chem. B
119
, 6225
(2015
).45.
O. H.
Ollila
, H. J.
Risselada
, M.
Louhivuori
, E.
Lindahl
, I.
Vattulainen
, and S. J.
Marrink
, “3D pressure field in lipid membranes and membrane-protein complexes
,” Phys. Rev. Lett.
102
, 078101
(2009
).46.
P. F. F.
Almeida
, W. L. C.
Vaz
, and T. E.
Thompson
, “Lateral diffusion in the liquid phases of dimyristoylphosphatidylcholine/cholesterol lipid bilayers: A free volume analysis
,” Biochemistry
31
, 6739
–6747
(1992
).47.
J.
Korlach
, P.
Schwille
, W. W.
Webb
, and G. W.
Feigenson
, “Characterization of lipid bilayer phases by confocal microscopy and fluorescence correlation spectroscopy
,” Proc. Natl. Acad. Sci. U. S. A.
96
, 8461
–8466
(1999
).48.
A.
Filippov
, G.
Oradd
, and G.
Lindblom
, “Domain formation in model membranes studied by pulsed-field gradient-NMR: The role of lipid polyunsaturation
,” Biophys. J.
93
, 3182
–3190
(2007
).49.
T.
Apajalahti
, P.
Niemela
, P. N.
Govindan
, M. S.
Miettinen
, E.
Salonen
, S. J.
Marrink
, and I.
Vattulainen
, “Concerted diffusion of lipids in raft-like membranes
,” Faraday Discuss.
144
, 411
–430
(2010
).50.
J. K.
Brennan
, M.
Lisal
, J. D.
Moore
, S.
Izvekov
, I. V.
Schweigert
, and J. P.
Larentzos
, “Coarse-grain model simulations of nonequilibrium dynamics in heterogeneous materials
,” J. Phys. Chem. Lett.
5
, 2144
(2014
).51.
V.
Agrawal
, P.
Peralta
, Y.
Li
, and J.
Oswald
, “Pressure-transferable coarse-grained potential for modeling the shock Hugoniot of polyethylene
,” J. Chem. Phys.
145
, 104903
(2016
).52.
S. H.
Min
and M. L.
Berkowitz
, “A comparative computational study of coarse-grained and all-atom water models in shock Hugoniot states
,” J. Chem. Phys.
148
, 144504
(2018
).53.
A.
Schroeder
, J.
Kost
, and Y.
Barenholz
, “Ultrasound, liposomes, and drug delivery: Principles for using ultrasound to control the Release of drugs from liposomes
,” Phys. Chem. Lipids
162
, 1
–16
(2009
).54.
B.
Krasovitski
, V.
Frenkel
, V.
Shoham
, and E.
Kimmel
, “Intramembrane cavitation as a unifying mechanism for ultrasound-induced bioeffects
,” Proc. Natl. Acad. Sci. U. S. A.
108
, 3258
(2011
).55.
H.
Okumura
and S. G.
Itoh
, “Amyloid fibril disruption by ultrasonic cavitation: Nonequilibrium molecular dynamics simulations
,” J. Am. Chem. Soc.
136
, 10549
–10552
(2014
).56.
C.
Aponte-Santamaria
, J.
Brunken
, and F.
Grater
, “Stress propagation through biological lipid bilayers in silico
,” J. Am. Chem. Soc.
139
, 13588
(2017
).57.
S. A.
Kirsch
and R. A.
Bockmann
, “Membrane pore formation in atomistic and coarse-grained simulations
,” Biochim. Biophys. Acta
1858
, 2266
(2016
).© 2019 Author(s).
2019
Author(s)
You do not currently have access to this content.