Although molecular dynamics (MD) simulations have been applied frequently to study flexible molecules, the sampling of conformational states separated by barriers is limited due to currently possible simulation time scales. Replica-exchange (Rex)MD simulations that allow for exchanges between simulations performed at different temperatures (T-RexMD) can achieve improved conformational sampling. However, in the case of T-RexMD the computational demand grows rapidly with system size. A Hamiltonian RexMD method that specifically enhances coupled dihedral angle transitions has been developed. The method employs added biasing potentials as replica parameters that destabilize available dihedral substates and was applied to study coupled dihedral transitions in nucleic acid molecules. The biasing potentials can be either fixed at the beginning of the simulation or optimized during an equilibration phase. The method was extensively tested and compared to conventional MD simulations and T-RexMD simulations on an adenine dinucleotide system and on a DNA abasic site. The biasing potential RexMD method showed improved sampling of conformational substates compared to conventional MD simulations similar to T-RexMD simulations but at a fraction of the computational demand. It is well suited to study systematically the fine structure and dynamics of large nucleic acids under realistic conditions including explicit solvent and ions and can be easily extended to other types of molecules.

1.
S.
Kirkpatrick
,
C. D.
Gelatt
, and
M. P.
Vecchi
,
Science
220
,
671
(
1983
).
2.
U. H.
Hansmann
,
Chem. Phys. Lett.
281
,
140
(
1997
).
3.
Y.
Sugita
and
Y.
Okamoto
,
Chem. Phys. Lett.
314
,
141
(
1999
).
4.
R.
Zhou
,
Methods Mol. Biol.
350
,
205
(
2007
).
5.
Y. M.
Rhee
and
V. S.
Pande
,
Biophys. J.
84
,
775
(
2003
).
6.
J. W.
Pitera
and
W.
Swope
,
Proc. Natl. Acad. Sci. U.S.A.
100
,
7587
(
2003
).
7.
W.
Nadler
and
U. H.
Hansmann
,
Phys. Rev. E
76
,
065701
(
2007
).
8.
C.
Kelso
and
C.
Simmerling
, in
Computational Studies of RNA and DNA
, edited by
J.
Sponer
and
F.
Lankas
(
Springer
,
Dordrecht, The Netherlands
,
2006
), pp.
147
168
.
9.
S.
Kannan
and
M.
Zacharias
,
Biophys. J.
93
,
3218
(
2007
).
10.
A. E.
Garcia
and
D.
Paschek
,
J. Am. Chem. Soc.
130
,
815
(
2008
).
11.
X.
Periole
and
A. E.
Mark
,
J. Chem. Phys.
126
,
014903
(
2007
).
12.
S.
Kannan
and
M.
Zacharias
,
Proteins
66
,
697
(
2007
).
13.
A.
Mitsutake
,
Y.
Sugita
, and
Y.
Okamoto
,
Biopolymers
60
,
96
(
2001
).
14.
Y.
Sugita
,
A.
Kitao
, and
Y.
Okamoto
,
J. Chem. Phys.
113
,
6042
(
2000
).
15.
M.
Zacharias
,
J. Chem. Theory Comput.
4
,
477
(
2008
).
16.
H.
Fukunishi
,
O.
Watanabe
, and
S.
Takada
,
J. Chem. Phys.
116
,
9058
(
2002
).
17.
W.
Kwak
and
U. H.
Hansmann
,
Phys. Rev. Lett.
95
,
138102
(
2005
).
18.
P.
Liu
,
B.
Kim
,
R. A.
Friesner
, and
B. J.
Berne
,
Proc. Natl. Acad. Sci. U.S.A.
102
,
13749
(
2005
).
19.
X.
Huang
,
M.
Hagen
,
B.
Kim
,
R. A.
Friesner
,
R.
Zhou
, and
B. J.
Berne
,
J. Phys. Chem.
111
,
5405
(
2007
).
20.
R.
Affentranger
,
I.
Tavernelli
, and
E. E.
Di Ioro
,
J. Chem. Theory Comput.
2
,
217
(
2006
).
21.
J. D.
Faraldo-Gómez
and
B.
Roux
,
J. Comput. Chem.
28
,
1634
(
2006
).
22.
G.
Chikenji
,
M.
Kikuchi
, and
Y.
Iba
,
Phys. Rev. Lett.
83
,
1886
(
1999
).
23.
Y.
Mu
,
Y.
Yang
, and
W.
Xu
,
J. Chem. Phys.
127
,
084119
(
2007
).
24.
D. L.
Beveridge
,
G.
Barreiro
,
K. S.
Byun
,
D. A.
Case
,
T. E.
Cheatham
 III
,
S. B.
Dixit
,
E.
Giudice
,
F.
Lankas
,
R.
Lavery
,
J. H.
Maddocks
,
R.
Osman
,
E.
Seibert
,
H.
Sklenar
,
G.
Stoll
,
K. M.
Thayer
,
P.
Varnai
, and
M. A.
Young
,
Biophys. J.
89
,
3721
(
2005
).
25.
S. B.
Dixit
,
D. L.
Beveridge
,
D. A.
Case
,
T. E.
Cheatham
 III
,
E.
Giudice
,
F.
Lankas
,
R.
Lavery
,
J. H.
Maddocks
,
R.
Osman
,
H.
Sklenar
,
K. M.
Thayer
, and
P.
Varnai
,
Biophys. J.
89
,
3721
(
2005
).
26.
P.
Varnai
and
K.
Zakrzewska
,
Nucleic Acids Res.
32
,
4269
(
2004
).
27.
D.
Svozil
,
J. E.
Sponer
,
I.
Marchan
,
A.
Perez
,
T. E.
Cheatham
 III
,
F.
Forti
,
F. J.
Luque
,
M.
Orozco
, and
J.
Sponer
,
J. Phys. Chem.
112
,
8188
(
2008
).
28.
N.
Metropolis
,
A. W.
Rosenbluth
,
M. N.
Rosenbluth
,
A. H.
Teller
, and
E. J.
Teller
,
J. Chem. Phys.
21
,
1087
(
1953
).
29.
D.
Djuranovic
and
B.
Hartmann
,
Biopolymers
73
,
356
(
2004
).
30.
M. J.
Packer
and
C. A.
Hunter
,
J. Mol. Biol.
280
,
407
(
1998
).
31.
H.
Bertrand
,
T.
Ha-Duong
,
S.
Fermandjian
, and
B.
Hartmann
,
Nucleic Acids Res.
26
,
1261
(
1998
).
32.
P.
Varnai
,
D.
Djuranovic
,
R.
Lavery
, and
B.
Hartmann
,
Nucleic Acids Res.
30
,
5398
(
2002
).
33.
J.
Chen
,
F. Y.
Dupradeau
,
D. A.
Case
,
C. J.
Turner
, and
J.
Stubbe
,
Biochemistry
46
,
3096
(
2007
).
34.
D. A.
Case
,
T. A.
Darden
,
T. E.
Cheatham
 III
,
C. L.
Simmerling
,
J.
Wang
,
R. E.
Duke
,
R.
Luo
,
K. M.
Maerz
,
B.
Wang
,
D. A.
Pearlman
,
M.
Crowley
,
S. R.
Brozell
,
V.
Tsui
,
H.
Golhlke
,
J.
Mongan
,
V.
Hornak
,
G.
Cui
,
P.
Beroza
,
C.
Schafmeister
,
J. W.
Caldwell
,
W. S.
Ross
, and
P. A.
Kollman
, University of California, San Francisco (
2004
).
35.
A.
Perez
,
I.
Marchan
,
D.
Svozil
,
J.
Sponer
,
T. E.
Cheatham
 III
,
C. A.
Laughton
, and
M.
Orozco
,
Biophys. J.
92
,
3817
(
2007
).
36.
T.
Darden
,
D.
York
, and
L.
Pedersen
,
J. Chem. Phys.
98
,
10089
(
1993
).
37.
T.
Hube
,
A. E.
Torda
, and
W. F.
vanGunsteren
,
J. Comput.-Aided Mol. Des.
8
,
695
(
1994
).
38.
A.
Laio
and
M.
Parrinello
,
Proc. Natl. Acad. Sci. U.S.A.
99
,
12562
(
2002
).
39.
P.
Raiteri
,
A.
Laio
,
F. L.
Gervasio
,
C.
Micheletti
, and
M.
Parinello
,
J. Phys. Chem.
110
,
3533
(
2006
).
40.
S.
Piana
and
A.
Laio
,
J. Phys. Chem.
111
,
4553
(
2007
).
41.
V.
Babin
,
C.
Roland
, and
C.
Sagui
,
J. Chem. Phys.
128
,
134101
(
2008
).
42.
B.
Demple
and
L.
Harrison
,
Annu. Rev. Biochem.
63
,
915
(
1994
).
43.
H.
Fujimoto
,
M.
Pinak
,
T.
Nemoto
,
P.
O’Neill
,
E.
Kume
,
K.
Saito
, and
H.
Maekawa
,
J. Comput. Chem.
26
,
788
(
2005
).
44.
L.
Ayadi
,
C.
Coulombeau
, and
R.
Lavery
,
Biophys. J.
77
,
3218
(
1999
).
You do not currently have access to this content.