Adhesive dynamics (AD) is a method for simulating the dynamic response of biological systems in response to force. Biological bonds are mechanical entities that exert force under strain, and applying forces to biological bonds modulates their rate of dissociation. Since small numbers of events usually control biological interactions, we developed a simple method for sampling probability distributions for the formation or failure of individual bonds. This method allows a simple coupling between force and strain and kinetics, while capturing the stochastic response of biological systems. Biological bonds are dynamically reconfigured in response to applied mechanical stresses, and a detailed spatio-temporal map of molecules and the forces they exert emerges from AD. The shape or motion of materials bearing the molecules is easily calculated from a mechanical energy balance provided the rheology of the material is known. AD was originally used to simulate the dynamics of adhesion of leukocytes under flow, but new advances have allowed the method to be extended to many other applications, including but not limited to the binding of viruses to surface, the clustering of adhesion molecules driven by stiff substrates, and the effect of cell-cell interaction on cell capture and rolling dynamics. The technique has also been applied to applications outside of biology. A particular exciting recent development is the combination of signaling with AD (so-called integrated signaling adhesive dynamics, or ISAD), which allows facile integration of signaling networks with mechanical models of cell adhesion and motility. Potential opportunities in applying AD are summarized.

References

References
1.
Hammer
,
D. A.
, and
Apte
,
S. M.
,
1992
, “
Simulation of Cell Rolling and Adhesion on Surfaces in Shear Flow: General Results and Analysis of Selectin-Mediated Neutrophil Adhesion
,”
Biophys. J.
,
63
, pp.
35
57
.10.1016/S0006-3495(92)81577-1
2.
Lawrence
,
M. B.
,
Berg
,
E. L.
,
Butcher
,
E. C.
, and
Springer
,
T. A.
,
1995
, “
Rolling of Lymphocytes and Neutrophils on Peripheral Node Addressing and Subsequent Arrest on ICAM-1 in Shear Flow
,”
Eur. J. Immunol.
,
25
, pp.
1025
1031
.10.1002/eji.1830250425
3.
Lawrence
,
M. B.
,
McIntire
,
L. V.
, and
Eskin
,
S. G.
,
1987
, “
Effect of Flow on Polymorphonuclear Leukocyte/Endothelial Cell Adhesion
,”
Blood
,
70
(
5
), pp.
1284
1290
.
4.
Tempelman
,
L. A.
, and
Hammer
,
D. A.
,
1994
, “
Receptor-Mediated Binding of IgE-Sensitized Rat Basophilic Leukemia Cells to Antigen-Coated Substrates Under Hydrodynamic Flow
,”
Biophys. J.
,
66
, pp.
1231
1243
.10.1016/S0006-3495(94)80907-5
5.
Bell
,
G. I.
,
1978
, “
Models for the Specific Adhesion of Cells to Cells
,”
Science
,
200
, pp.
618
627
.10.1126/science.347575
6.
Beste
,
M. T.
, and
Hammer
,
D. A.
,
2008
, “
Selectin Catch-Slip Kinetics Encode Shear Threshold Adhesive Behavior of Rolling Leukocytes
,”
Proc. Natl. Acad. Sci. U.S.A.
,
105
(
52
), pp.
20716
20721
.10.1073/pnas.0808213105
7.
Hammer
,
D. A.
, and
Lauffenburger
,
D. A.
,
1987
, “
A Dynamic Model for Receptor-Mediated Cell Adhesion to Surfaces
,”
Biophys. J.
,
52
, pp.
475
487
.10.1016/S0006-3495(87)83236-8
8.
Dembo
,
M.
,
Torney
,
D. C.
,
Saxman
,
K.
, and
Hammer
,
D. A.
,
1988
, “
The Reaction-Limited Kinetics of Membrane-to-Surface Adhesion and Detachment
,”
Proc. R. Soc. London, Ser. B
,
234
, pp.
55
83
.10.1098/rspb.1988.0038
9.
Chan
,
C. E.
, and
Odde
,
D. J.
,
2008
, “
Traction Dynamics of Filopodia on Compliant Substrates
,”
Science
,
322
(
5908
), pp.
1687
1691
.10.1126/science.1163595
10.
Bruehl
,
R. E.
,
Springer
,
T. A.
, and
Bainton
,
D. F.
,
1996
, “
Quantitation of L-Selectin Distribution on Human Leukocyte Microvilli by Immunogold Labeling and Electron Microscopy
,”
J. Histochem. Cytochem.
,
44
(
8
), pp.
835
844
.10.1177/44.8.8756756
11.
Picker
,
L. J.
,
Warnock
,
R. A.
,
Burns
,
A. R.
,
Doerschuk
,
C. M.
,
Berg
,
E. L.
, and
Butcher
,
E. C.
,
1991
, “
The Neutrophil Selectin LECAM-1 Presents Carbohydrate Ligands to the Vascular Selectins ELAM-1 and GMP-140
,”
Cell
,
66
(
5
), pp.
921
933
.10.1016/0092-8674(91)90438-5
12.
Bussell
,
S. J.
,
Koch
,
D. L.
, and
Hammer
,
D. A.
,
1995
, “
The Effect of Hydrodynamic Interactions on the Diffusion of Integral Membrane Proteins. Diffusion in Plasma Membranes
,”
Biophys. J.
,
68
, pp.
1836
1849
.10.1016/S0006-3495(95)80360-7
13.
Chang
,
K. C.
,
Tees
,
D. F. J.
, and
Hammer
,
D. A.
,
2000
, “
The State Diagram for Cell Adhesion Under Flow: Leukocyte Rolling and Firm Adhesion
,”
Proc. Natl. Acad. Sci. U.S.A.
,
97
(
21
), pp.
11262
11267
.10.1073/pnas.200240897
14.
Alon
,
R.
,
Hammer
,
D. A.
, and
Springer
,
T. A.
,
1995
, “
Lifetime of the P-selectin: Carbohydrate Bond and its Response to Tensile Force in Hydrodynamic Flow
,”
Nature
,
374
, pp.
539
542
.10.1038/374539a0
15.
King
,
M. R.
, and
Hammer
,
D. A.
,
2001
, “
Multiparticle Adhesive Dynamics. Interactions Between Stably Rolling Cells
,”
Biophys. J.
,
81
(
2
), pp.
799
813
.10.1016/S0006-3495(01)75742-6
16.
King
,
M. R.
,
Kim
,
M. B.
,
Sarelius
,
I. H.
, and
Hammer
,
D. A.
,
2003
, “
Hydrodynamic Interactions Between Rolling Leukocytes in vivo
,”
Microcirculation
,
10
, pp.
401
409
.
17.
Brunk
,
D. K.
, and
Hammer
,
D. A.
,
1997
, “
Quantifying Rolling Adhesion With a Cell-Free Assay: E-Selectin and its Carbohydrate Ligands
,”
Biophys. J.
,
72
(
6
), pp.
2820
2833
.10.1016/S0006-3495(97)78924-0
18.
Chang
,
K. C.
, and
Hammer
,
D. A.
,
2000
, “
Adhesive Dynamics Simulations of Sialyl-Lewis(x)/E-Selectin- Mediated Rolling in a Cell-Free System
,”
Biophys. J.
,
79
(
4
), pp.
1891
1902
.10.1016/S0006-3495(00)76439-3
19.
Lipowsky
,
H.
,
Riedel
,
H. D.
, and
Shi
,
G. S.
,
1991
, “
in vivo Mechanical Properties of Leukocytes During Adhesion to Venular Endothelium
,”
Biorheology
,
28
(
1–2
), pp.
53
64
.
20.
Evans
,
E.
,
Leung
,
A.
,
Hammer
,
D.
, and
Simon
,
S.
,
2001
, “
Chemically Distinct Transition States Govern Rapid Dissociation of Single L-Selectin Bonds Under Force
,”
Proc. Natl. Acad. Sci. U.S.A.
,
98
(
7
), pp.
3784
3789
.10.1073/pnas.061324998
21.
Finger
,
E. B.
,
Puri
,
K. D.
,
Alon
,
R.
,
Lawrence
,
M. B.
,
von Andrian
,
U.
, and
Springer
,
T. A.
,
1996
, “
Adhesion Through L-Selectin Requires a Threshold Hydrodynamic Shear
,”
Nature
,
379
, pp.
266
269
.10.1038/379266a0
22.
Chang
,
K.-C.
, and
Hammer
,
D. A.
,
1999
, “
The Forward Rate of Binding of Surface-Tethered Reactants: Effect of Relative Motion Between Two Surfaces
,”
Biophys. J.
,
76
, pp.
1280
1292
.10.1016/S0006-3495(99)77291-7
23.
Caputo
,
K. E.
,
Lee
,
D.
,
King
,
M. R.
, and
Hammer
,
D. A.
,
2007
, “
Adhesive Dynamics Simulations of the Shear Threshold Effect for Leukocytes
,”
Biophys. J.
,
92
(
3
), pp.
787
797
.10.1529/biophysj.106.082321
24.
Lu
,
C.
,
Shimaoka
,
M.
,
Ferzly
,
M.
,
Oxvig
,
C.
,
Takagi
,
J.
, and
Springer
,
T. A.
, “
An Isolated, Surface-Expressed I-Domain of the Integrin AlphaLbeta2 is Sufficient for Strong Adhesive Function When Locked in the Open Conformation With a Disulfide Bond
,”
Proc. Natl. Acad. Sci. U.S.A.
,
98
, pp.
2387
2392
.10.1073/pnas.041606398
25.
Eniola
,
A. O.
,
Willcox
,
J.
, and
Hammer
,
D. A.
,
2003
, “
Interplay Between Rolling and Firm Adhesion Elucidated With a Cell-Free System Engineered With Two Distinct Receptor-Ligand Pairs
,”
Biophys. J.
,
85
, pp.
2720
2731
.10.1016/S0006-3495(03)74695-5
26.
Bhatia
,
S. K.
,
King
,
M. R.
, and
Hammer
,
D. A.
,
2003
, “
The State Diagram for Cell Adhesion Mediated by Two Receptors
,”
Biophys. J.
,
84
, pp.
2671
2690
.10.1016/S0006-3495(03)75073-5
27.
Alon
,
R.
, and
Ley
,
K.
,
2008
, “
Cells on the Run: Shear-Regulated Integrin Activation in Leukocyte Rolling and Arrest on Endothelial Cells
,”
Curr. Opin. Cell Biol.
,
20
, pp.
1
8
.10.1016/j.ceb.2008.04.003
28.
Morrison
,
V. L.
,
Macpherson
,
M. T.
,
Savinko
,
T.
,
San Lek
,
H.
,
Prescott
,
A.
, and
Fagerholm
,
S. C.
,
2013
, “
The Beta2 Integrin-kindlin-3 Interaction is Essential for T-cell Homing but Dispensable for T-Cell Activation in vivo
,”
Blood
,
122
(
8
), pp.
1428
1436
.10.1182/blood-2013-02-484998
29.
Krasik
,
E. F.
,
Caputo
,
K. E.
, and
Hammer
,
D. A.
,
2008
, “
Adhesive Dynamics Simulations of Neutrophil Arrest With Stochastic Activation
,”
Biophys. J.
,
95
(
4
), pp.
1716
1728
.10.1529/biophysj.107.119677
30.
Krasik
,
E. F.
,
Yee
,
K. Y.
, and
Hammer
,
D. A.
,
2006
, “
Adhesive Dynamics Simulation of Neutrophil Arrest With Deterministic Activation
,”
Biophys. J.
,
91
, pp.
1145
1155
.10.1529/biophysj.105.070706
31.
Caputo
,
K. E.
, and
Hammer
,
D. A.
,
2008
, “
Adhesive Dynamics Simulation of G-protein-mediated Chemokine-activated Neutrophil Adhesion
,”
Biophys. J.
(submitted).
32.
Beste
,
M. T.
,
Lee
,
D.
,
King
,
M. R.
,
Koretzky
,
G. A.
, and
Hammer
,
D. A.
,
2012
, “
An Integrated Stochastic Model of ‘Inside-Out’ Integrin Activation and Selective T-lymphocyte Recruitment
,”
Langmuir
,
28
(
4
), pp.
2225
2237
.10.1021/la203803e
33.
Gillespie
,
D. T.
,
1975
, “
Exact Method for Numerically Simulating Stochastic Coalescence Process in a Cloud
,”
J. Atmos. Sci.
,
32
(
10
), pp.
1977
1989
.10.1175/1520-0469(1975)032<1977:AEMFNS>2.0.CO;2
34.
Shao
,
J.-Y.
,
Ting-Beall
,
H. P.
, and
Hochmuth
,
R. M.
,
1998
, “
Static and Dynamic Lengths of Neutrophil Microvilli
,”
Proc. Natl. Acad. Sci.
,
95
, pp.
6797
6802
.10.1073/pnas.95.12.6797
35.
Jadhav
,
S.
,
Eggleton
,
C. D.
, and
Konstantopoulos
,
K.
,
2005
, “
A 3-D Computational Model Predicts That Cell Deformation Affects Selectin-Mediated Leukocyte Rolling
,”
Biophys. J.
,
88
(
1
), pp.
96
104
.10.1529/biophysj.104.051029
36.
Caputo
,
K. E.
, and
Hammer
,
D. A.
,
2005
, “
Effect of Microvillus Deformability on Leukocyte Adhesion Explored Using Adhesive Dynamics Simulations
,”
Biophys. J.
,
89
, pp.
187
200
.10.1529/biophysj.104.054171
37.
Khismatullin
,
D. B.
, and
Truskey
,
G. A.
,
2005
, “
Three-Dimensional Numerical Simulation of Receptor-Mediated Leukocyte Adhesion to Surfaces: Effects of Cell Deformability and Viscoelasticity
,”
Phys. Fluids
,
17
, p.
031505
.10.1063/1.1862635
38.
King
,
M. R.
,
Rodgers
,
S. D.
, and
Hammer
,
D. A.
,
2001
, “
Hydrodynamic Collisions Suppress Fluctuations in the Rolling Velocity of Adhesive Blood Cells
,”
Langmuir
,
17
(
14
), pp.
4139
4143
.10.1021/la010234b
39.
King
,
M. R.
, and
Hammer
,
D. A.
,
2001
, “
Multiparticle Adhesive Dynamics: Hydrodynamic Recruitment of Rolling Leukocytes
,”
Proc. Natl. Acad. Sci. U.S.A
,
98
(
26
), pp.
14919
14924
.10.1073/pnas.261272498
40.
Isfahani
,
A. H.
, and
Freund
,
J. B.
,
2012
, “
Forces on a Wall-Bound Leukocyte in a Small Vessel Due to Red Cells in the Blood Stream
,”
Biophys. J.
,
103
(
7
), pp.
1604
1615
.10.1016/j.bpj.2012.08.049
41.
Mody
,
N. A.
, and
King
,
M. R.
,
2007
, “
Influence of Brownian Motion on Blood Platelet Flow Behavior and Adhesive Dynamics Near a Planar Wall
,”
Langmuir
,
23
(
11
), pp.
6321
6328
.10.1021/la0701475
42.
Mody
,
N. A.
, and
King
,
M. R.
,
2008
, “
Platelet Adhesive Dynamics. Part I: Characterization of Platelet Hydrodynamic Collisions and Wall Effects
,”
Biophys. J.
,
95
(
5
), pp.
2539
2555
.10.1529/biophysj.107.127670
43.
Mody
,
N. A.
, and
King
,
M. R.
,
2008
, “
Platelet Adhesive Dynamics. Part II: High Shear-Induced Transient Aggregation via GPIbalpha-vWF-GPIbalpha Bridging
,”
Biophys. J.
,
95
(
5
), pp.
2556
2574
.10.1529/biophysj.107.128520
44.
Mody
,
N. A.
,
Lomakin
,
O.
,
Doggett
,
T. A.
,
Diacovo
,
T. G.
, and
King
,
M. R.
,
2005
, “
Mechanics of Transient Platelet Adhesion to von Willebrand Factor Under Flow
,”
Biophys. J.
,
88
(
2
), pp.
1432
1443
.10.1529/biophysj.104.047001
45.
Wang
,
W.
,
Mody
,
N. A.
, and
King
,
M. R.
,
2013
, “
Multiscale Model of Platelet Translocation and Collision
,”
J. Comput. Phys.
,
244
, pp.
223
235
.10.1016/j.jcp.2012.08.014
46.
Fedosov
,
D. A.
,
Caswell
,
B.
, and
Karniadakis
,
G. E.
,
2010
, “
A Multiscale Red Blood Cell Model With Accurate Mechanics, Rheology, and Dynamics
,”
Biophys. J.
,
98
(
10
), pp.
2215
2225
.10.1016/j.bpj.2010.02.002
47.
Fedosov
,
D. A.
,
Caswell
,
B.
, and
Karniadakis
,
G. E.
,
2011
, “
Wall Shear Stress-Based Model for Adhesive Dynamics of Red Blood Cells in Malaria
,”
Biophys. J.
,
100
(
9
), pp.
2084
2093
.10.1016/j.bpj.2011.03.027
48.
Fedosov
,
D. A.
,
Caswell
,
B.
,
Suresh
,
S.
, and
Karniadakis
,
G. E.
,
2011
, “
Quantifying the Biophysical Characteristics of Plasmodium-Falciparum-Parasitized Red Blood Cells in Microcirculation
,”
Proc. Natl. Acad. Sci. U.S.A.
,
108
(
1
), pp.
35
39
.10.1073/pnas.1009492108
49.
Fedosov
,
D. A.
,
Lei
,
H.
,
Caswell
,
B.
,
Suresh
,
S.
, and
Karniadakis
,
G. E.
,
2011
, “
Multiscale Modeling of Red Blood Cell Mechanics and Blood Flow in Malaria
,”
PLoS Comput. Biol.
,
7
(
12
), p.
e1002270
10.1371/journal.pcbi.1002270.
50.
Pan
,
W.
,
Fedosov
,
D. A.
,
Caswell
,
B.
, and
Karniadakis
,
G. E.
,
2011
, “
Predicting Dynamics and Rheology of Blood Flow: A Comparative Study of Multiscale and Low-Dimensional Models of Red Blood Cells
,”
Microvasc. Res.
,
82
(
2
), pp.
163
170
.10.1016/j.mvr.2011.05.006
51.
English
,
T. J.
, and
Hammer
,
D. A.
,
2005
, “
The Effect of Cellular Receptor Diffusion on Receptor-Mediated Viral Binding Using Brownian Adhesive Dynamics (BRAD) Simulations
,”
Biophys. J.
,
88
(
3
), pp.
1666
1675
.10.1529/biophysj.104.047043
52.
English
,
T. J.
, and
Hammer
,
D. A.
,
2004
, “
Brownian Adhesive Dynamics (BRAD) for Simulating the Receptor-Mediated Binding of Viruses
,”
Biophys. J.
,
86
(
6
), pp.
3359
3372
.10.1529/biophysj.103.027813
53.
Paszek
,
M.
,
Boettiger
,
D.
,
Weaver
,
V. M.
, and
Hammer
,
D. A.
,
2009
, “
Integrin Clustering is Driven by Mechanical Resistance From the Glycocalyx and the Substrate
,”
PLoS Comput. Biol.
,
5
(
12
), p.
e1000604
.10.1371/journal.pcbi.1000604
54.
Wang
,
W.
,
Mody
,
N. A.
, and
King
,
M. K.
,
2013
, “
Multiscale Model of Platelet Translocation and Collision
,”
J. Comput. Phys.
,
244
, pp.
223
235
.10.1016/j.jcp.2012.08.014
55.
Lei
,
H.
, and
Karniadakis
,
G. E.
,
2013
, “
Probing Vasoocclusion Phenomena in Sickle Cell Anemia Via Mesoscopic Simulations
,”
Proc. Natl. Acad. Sci. U S A
,
110
(
28
), pp.
11326
11330
.10.1073/pnas.1221297110
56.
Hlavacek
,
W. S.
,
Posner
,
R. G.
, and
Perelson
,
A. S.
,
1999
, “
Steric Effects on Multivalent Ligand-Receptor Binding: Exclusion of Ligand Sites by Bound Cell Surface Receptors
,”
Biophys. J.
,
76
(
6
), pp.
3031
3043
.10.1016/S0006-3495(99)77456-4
57.
Trister
,
A. D.
, and
Hammer
,
D. A.
,
2008
, “
Role of gp120 Trimerization on HIV Binding Elucidated With Brownian Adhesive Dynamics
,”
Biophys. J.
,
95
(
1
), pp.
40
53
.10.1529/biophysj.107.118430
58.
Chan
,
C. E.
, and
Odde
,
D. J.
,
2008
, “
Traction Dynamics of Filopodia on Compliant Substrates
,”
Science
,
322
(
5908
), pp.
1687
1691
.10.1126/science.1163595
59.
Paszek
,
M.
,
Zahir
,
N.
,
Johnson
,
K. R.
,
Lakins
,
J. N.
,
Rozenberg
,
G. I.
,
Gefen
,
A.
,
Reinhart-King
,
C. A.
,
Margulies
,
S. S.
,
Dembo
,
M.
,
Boettinger
,
D.
,
Hammer
,
D. A.
, and
Weaver
,
V.
,
2005
, “
Tensional Homeostasis and the Malignant Phenotype
,”
Cancer Cell
,
8
, pp.
241
254
.10.1016/j.ccr.2005.08.010
60.
Timpe
,
L. C.
,
Yen
,
R.
,
Haste
,
N. V.
,
Litsakos-Cheung
,
C.
,
Yen
,
T. Y.
, and
Macher
,
B. A.
,
2013
, “
Systemic Alteration of Cell-Surface and Secreted Glycoprotein Expression in Malignant Breast Cancer Cell Lines
,”
Glycobiology
,
11
, pp.
1240
1249
.
61.
Ward
,
M. D.
, and
Hammer
,
D. A.
,
1993
, “
Morphology of Cell-substratum Adhesion: Influence of Receptor Heterogeneity and Nonspecific Forces
,”
Cell Biophys.
,
20
, pp.
177
222
.
62.
Wang
,
Y.-K.
, and
Chen
,
C. S.
,
2013
, “
Cell Adhesion and Mechanical Stimulation in the Regulation of Mesenchymal Stem Cell Differentiation
,”
Journal of Cellular and Molecular Medicine
,
27
(7), pp.
823
832
.
63.
Zhao
,
T.
,
Li
,
Y.
, and
Dinner
,
A. R.
,
2009
, “
How Focal Adhesion Size Depends on Integrin Affinity
,”
Langmuir
,
25
(
3
), pp.
1540
1546
.10.1021/la8026804
64.
Yang
,
M. T.
,
Sniadecki
,
N. J.
, and
Chen
,
C. S.
,
2007
, “
Geometric Considerations of Micro- to Nanoscale Elastomeric Post Arrays to Study Cellular Traction Forces
,”
Adv. Mater.
,
19
(
20
), pp.
3119
3123
.10.1002/adma.200701956
65.
Gimona
,
M. R.
,
Buccione
,
S. A.
,
Courtneidge
, and
Linder
,
S.
,
2008
, “
Assembly and Biological Role of Podosomes and Invadopodia
,”
Curr. Opin. Cell Biol.
,
20
(
2
), pp.
235
241
.10.1016/j.ceb.2008.01.005
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