Cell adhesion complexes (CACs), which are activated by ligand binding, play key roles in many cellular functions ranging from cell cycle regulation to mediation of cell extracellular matrix adhesion. Inspired by single molecule pulling experiments using atomic force spectroscopy on leukocyte function-associated antigen-1 (LFA-1), expressed in T-cells, bound to intercellular adhesion molecules (ICAM), we performed constant loading rate (rf) and constant force (F) simulations using the self-organized polymer model to describe the mechanism of ligand rupture from CACs. The simulations reproduce the major experimental finding on the kinetics of the rupture process, namely, the dependence of the most probable rupture forces (f*s) on ln rf (rf is the loading rate) exhibits two distinct linear regimes. The first, at low rf, has a shallow slope, whereas the slope at high rf is much larger, especially for a LFA-1/ICAM-1 complex with the transition between the two occurring over a narrow rf range. Locations of the two transition states (TSs) extracted from the simulations show an abrupt change from a high value at low rf or constant force, F, to a low value at high rf or F. This unusual behavior in which the CACs switch from one brittle (TS position is a constant over a range of forces) state to another brittle state is not found in forced-rupture in other protein complexes. We explain this novel behavior by constructing the free energy profiles, F(Λ)s, as a function of a collective reaction coordinate (Λ), involving many key charged residues and a critical metal ion (Mg2+). The TS positions in F(Λ), which quantitatively agree with the parameters extracted using the Bell-Evans model, change abruptly at a critical force, demonstrating that it, rather than the molecular extension, is a good reaction coordinate. Our combined analyses using simulations performed in both the pulling modes (constant rf and F) reveal a new mechanism for the two loading regimes observed in the rupture kinetics in CACs.

2.
W.
Somers
,
J.
Tang
,
G.
Shaw
, and
R.
Camphausen
,
Cell
103
,
467
479
(
2000
).
3.
G. F.
Weber
,
M. A.
Bjerke
, and
D. W.
DeSimone
,
J. Cell Sci.
124
,
1183
1193
(
2011
).
4.
B.-H.
Luo
,
C. V.
Carman
, and
T. A.
Springer
,
Annu. Rev. Immunol.
25
,
619
647
(
2007
).
5.
E. P.
Wojcikiewicz
,
M. H.
Abdulreda
,
X.
Zhang
, and
V. T.
Moy
,
Biomacromolecules
7
,
3188
3195
(
2006
).
6.
R.
Merkel
,
P.
Nassoy
,
A.
Leung
,
K.
Ritchie
, and
E.
Evans
,
Nature
397
,
50
53
(
1999
).
7.
E.
Evans
,
Annu. Rev. Biophys. Biomol. Struct.
30
,
105
128
(
2001
).
8.
C. M.
Franz
,
A.
Taubenberger
,
P.-H.
Puech
, and
D. J.
Muller
,
Sci. STKE
406
,
pl5
(
2007
).
9.
A.
Taubenberger
,
D. A.
Cisneros
,
J.
Friedrichs
,
P.-H.
Puech
,
D. J.
Muller
, and
C. M.
Franz
,
Mol. Biol. Cell
18
,
1634
1644
(
2007
).
10.
G. I.
Bell
,
Science
200
,
618
627
(
1978
).
11.
E.
Evans
and
K.
Ritchie
,
Biophys. J.
72
,
1541
1555
(
1997
).
12.
C.
Hyeon
and
D.
Thirumalai
,
J. Chem. Phys.
137
,
055103
(
2012
).
13.
C.
Hyeon
,
R. I.
Dima
, and
D.
Thirumalai
,
Structure
14
,
1633
1645
(
2006
).
14.
M.
Mickler
,
R. I.
Dima
,
H.
Dietz
,
C.
Hyeon
,
D.
Thirumalai
, and
M.
Rief
,
Proc. Natl. Acad. Sci. U. S. A.
104
,
20268
20273
(
2007
).
15.
O.
Kononova
,
Y.
Kholodov
,
K. E.
Theisen
,
K. A.
Marx
,
R. I.
Dima
,
F. I.
Ataullakhanov
,
E. L.
Grishchuk
, and
V.
Barsegov
,
J. Am. Chem. Soc.
136
,
17036
17045
(
2014
).
16.
A.
Zhmurov
,
A. E.
Brown
,
R. I.
Litvinov
,
R. I.
Dima
,
J. W.
Weisel
, and
V.
Barsegov
,
Structure
19
,
1615
1624
(
2011
).
17.
H.
Joshi
,
F.
Momin
,
K. E.
Haines
, and
R. I.
Dima
,
Biophys. J.
98
,
657
666
(
2010
).
18.
D.
Bauer
,
D. R.
Merz
,
B.
Pelz
,
K. E.
Theisen
,
G.
Yacyshyn
,
D.
Mokranjac
,
R. I.
Dima
,
M.
Rief
, and
G.
Zoldak
,
Proc. Natl. Acad. Sci. U. S. A.
112
,
10389
10394
(
2015
).
19.
P. I.
Zhuravlev
,
G.
Reddy
,
J. E.
Straub
, and
D.
Thirumalai
,
J. Mol. Biol.
426
,
2653
2666
(
2014
).
20.
J.
Chen
,
S. A.
Darst
, and
D.
Thirumalai
,
Proc. Natl. Acad. Sci. U. S. A.
107
,
12523
12528
(
2010
).
21.
N.
Hori
,
N. A.
Denesyuk
, and
D.
Thirumalai
,
J. Mol. Biol.
428
,
2847
2859
(
2016
).
22.
C.
Hyeon
and
D.
Thirumalai
,
J. Phys.: Condens. Matter
19
,
113101
(
2007
).
23.
D. K.
Klimov
and
D.
Thirumalai
,
Proc. Natl. Acad. Sci. U. S. A.
97
,
7254
7259
(
2000
).
24.
G.
Song
,
Y.
Yang
,
J.-H.
Liu
,
J. M.
Casasnovas
,
M.
Shimaoka
,
T. A.
Springer
, and
J.-h.
Wang
,
Proc. Natl. Acad. Sci. U. S. A.
102
,
3366
3371
(
2005
).
25.
P. I.
Zhuravlev
,
M.
Hinczewski
,
S.
Chakrabarti
,
S.
Marqusee
, and
D.
Thirumalai
,
Proc. Natl. Acad. Sci. U. S. A.
113
,
E715
E724
(
2016
).
26.
B. T.
Marshall
,
M.
Long
,
J. W.
Piper
,
T.
Yago
,
R. P.
McEver
, and
C.
Zhu
,
Nature
423
,
190
193
(
2003
).
27.
K.
Sarangapani
,
T.
Yago
,
A.
Klopocki
,
M.
Lawrence
,
C.
Fieger
,
S.
Rosen
,
R.
McEver
, and
C.
Zhu
,
J. Biol. Chem.
279
,
2291
2298
(
2004
).
28.
V.
Barsegov
and
D.
Thirumalai
,
J. Phys. Chem. B
110
,
26403
26412
(
2006
).
29.
D. L.
Huang
,
N. A.
Bax
,
C. D.
Buckley
,
W. I.
Weis
, and
A. R.
Dunn
,
Science
357
,
703
706
(
2017
).
30.
C. D.
Buckley
,
J.
Tan
,
K. L.
Anderson
,
D.
Hanein
,
N.
Volkmann
,
W. I.
Weis
,
W. J.
Nelson
, and
A. R.
Dunn
,
Science
346
,
1254211
(
2014
).
31.
V. C.
Luca
,
B. C.
Kim
,
C.
Ge
,
S.
Kakuda
,
D.
Wu
,
M.
Roein-Peikar
,
R. S.
Haltiwanger
,
C.
Zhu
,
T.
Ha
, and
K. C.
Garcia
,
Science
355
,
1320
1324
(
2017
).
32.
V.
Barsegov
and
D.
Thirumalai
,
Proc. Natl. Acad. Sci. U. S. A.
102
,
1835
1839
(
2005
).
33.
W.
Thomas
,
V.
Vogel
, and
E.
Sokurenko
,
Annu. Rev. Biophys.
37
,
399
416
(
2008
).
34.
S.
Chakrabarti
,
M.
Hinczewski
, and
D.
Thirumalai
,
J. Struct. Biol.
197
,
50
56
(
2017
).
35.
S.
Chakrabarti
,
M.
Hinczewski
, and
D.
Thirumalai
,
Proc. Natl. Acad. Sci. U. S. A.
111
,
9048
9053
(
2014
).
36.
O. K.
Dudko
,
G.
Hummer
, and
A.
Szabo
,
Phys. Rev. Lett.
96
,
108101
(
2006
).
37.
P.
Cossio
,
G.
Hummer
, and
A.
Szabo
,
Biophys. J.
111
,
832
840
(
2016
).
38.
N.
Lee
and
D.
Thirumalai
,
Macromolecules
34
,
3446
3457
(
2001
).
39.
E.
Koculi
,
C.
Hyeon
,
D.
Thirumalai
, and
S. A.
Woodson
,
J. Am. Chem. Soc.
129
,
2676
2682
(
2007
).
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