In this study we report on the application of the diffusion process-controlled Monte Carlo method to a 20 amino acid αβ peptide (Ac-E-T-Q-A-A-L-L-A-A-Q-K-A-Y-H-P-M-T-M-T-G-Am). The polypeptide chain is represented by a set of 126 particles, the side chains are modeled by spheres, and the backbone dihedral angles φ and ψ of each of the amino acid residue are essentially restricted to a set of ten high probability regions, although the whole φ-ψ space may be visited in the course of the simulation. The method differs from other off-lattice Monte Carlo methods, in that the escape time from one accepted conformation to the next is estimated and limited at each iteration. The conformations are evaluated on the basis of pairwise nonbonded side chain energies derived from statistical distributions of contacts in real proteins and a simple main chain hydrogen bonding potential. As a result of four simulations starting from random extended conformations and one starting from a structure consistent with NMR data, the lowest-energy conformation (i.e., the αβ fold) is detected in ∼103 Monte Carlo steps, although the estimated probability of getting the αβ motif is ∼10−12. The predicted conformations deviate by 3.0 Å rms from a model structure compatible with the experimental results. In this work further evidence is provided that this method is useful in determining the lowest-energy region of medium-size polypeptide chains.

1.
M.
Levitt
and
A.
Warshel
,
Nature (London)
253
,
694
(
1975
).
2.
A. T.
Hagler
and
B.
Honig
,
Proc. Natl. Acad. Sci. USA
75
,
554
(
1978
).
3.
M. H.
Lambert
and
H. A.
Scheraga
,
J. Comput. Chem.
10
,
770
(
1989
).
4.
A.
Kolinski
and
J.
Skolnick
,
Proteins Struct., Funct., Gen.
18
,
338
(
1994
).
5.
Z.
Li
and
H. A.
Scheraga
,
J. Mol. Struct. Theochem.
179
,
333
(
1988
).
6.
R.
Abagyan
and
M.
Totrov
,
J. Mol. Biol.
235
,
983
(
1994
).
7.
J. S.
Evans
,
A. M.
Mathiowetz
,
S. I.
Chan
, and
W.
Goddard
, III
,
Protein Sci.
4
,
1203
(
1995
).
8.
F.
Avbelj
and
J.
Moult
,
Proteins Struct., Funct., Gen.
23
,
129
(
1995
).
9.
A.
Wallqvist
and
M.
Ullner
,
Proteins Struct., Funct., Gen.
18
,
267
(
1994
).
10.
A.
Liwo
,
M. R.
Pincus
,
R. J.
Wawak
,
S.
Rackovsky
, and
H. A.
Scheraga
,
Protein Sci.
2
,
1715
(
1993
).
11.
R.
Srinivasan
and
G. D.
Rose
,
Proteins Struct., Funct., Gen.
22
,
81
(
1995
).
12.
C.
Wilson
and
S.
Doniach
,
Proteins Struct., Funct., Gen.
6
,
193
(
1989
).
13.
T.
Karasawa
,
K.
Tabuchi
,
M.
Fumoto
, and
T.
Yasukawa
,
Comput. Appl. Biosci.
9
,
243
(
1993
).
14.
K.
Yue
and
K.
Dill
,
Protein Sci.
5
,
224
(
1996
).
15.
S.
Sun
,
P. D.
Thomas
, and
K. A.
Dill
,
Protein Eng.
8
,
769
(
1995
).
16.
P.
Derreumaux
,
J. Chem. Phys.
106
,
5260
(
1997
).
17.
N. S.
Metropolis
,
A. W.
Rosenbluth
,
M. N.
Rosenbluth
,
A. H.
Teller
, and
E.
Teller
,
J. Chem. Phys.
21
,
1087
(
1953
).
18.
D. J.
Butcher
,
M. D.
Bruch
, and
G. R.
Moe
,
Biopolymers
35
,
109
(
1995
).
19.
D. J.
Butcher
and
G. R.
Moe
,
Proc. Natl. Acad. Sci. USA
93
,
1135
(
1996
).
20.
M.
Levitt
,
J. Mol. Biol.
104
,
59
(
1976
).
21.
E. G.
Hutchinson
and
J. M.
Thornton
,
Protein Sci.
3
,
2207
(
1994
).
22.
S.
Miyazawa
and
R. L.
Jernigan
,
Macromolecules
18
,
534
(
1985
).
23.
D. G.
Covell
and
R. L.
Jernigan
,
Biochemistry
29
,
3287
(
1990
).
24.
A.
Godzik
,
A.
Kolinski
, and
J.
Skolnick
,
Protein Sci.
4
,
2107
(
1995
).
25.
L. A.
Mirny
and
E. I.
Shakhnovich
,
J. Mol. Biol.
264
,
1164
(
1996
).
26.
C. B.
Anfinsen
,
Science
181
,
223
(
1973
).
27.
M. J.
Rooman
,
J-P. A.
Kocher
, and
S. J.
Wodak
,
J. Mol. Biol.
221
,
961
(
1991
).
28.
A.
Sali
,
E.
Shakhnovich
, and
M.
Karplus
,
J. Mol. Biol.
235
,
1614
(
1994
).
29.
E. N.
Baker
and
R. E.
Hubbard
,
Progr. Biophys. Mol. Biol.
44
,
97
(
1984
).
30.
W.
Kabsch
and
C.
Sander
,
Biopolymers
22
,
2577
(
1983
).
31.
S. J.
Weiner
,
P. A.
Kollman
,
D. A.
Case
,
U. C.
Singh
,
C.
Ghio
,
G.
Alagona
,
S.
Profeta
, and
P.
Weiner
,
J. Am. Chem. Soc.
106
,
765
(
1984
).
32.
The minimization with the AMBER force field considers that the force constants related to the change in the bond lengths of the side chains are set to 400 kcal/(mol Å2), the peptide bonds are forced to be trans with a harmonic potential using a force constant of 17 kcal/(molrad2), the charge for each side-chain centroid is equal to the AMBER charge for the corresponding group of atoms, the 1–4 nonbonded (vicinal) Lennard-Jones interactions are divided by 8.0 and the 1–4 Coulombic interactions are divided by 2.0, as recommended for protein compaction, a cutoff of 12.0 Å is used for the evaluation of all pair interactions, and the dielectric function is set to 2r.
33.
K. A.
Dill
,
Biochemistry
24
,
1501
(
1985
).
34.
P. L.
Privalov
,
Adv. Protein Chem.
33
,
167
(
1979
).
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