We present a technique for biomolecular free energy calculations that exploits highly parallelized sampling to significantly reduce the time to results. The technique combines free energies for multiple, nonoverlapping configurational macrostates and is naturally suited to distributed computing. We describe a methodology that uses this technique with docking, molecular dynamics, and free energy perturbation to compute absolute free energies of binding quickly compared to previous methods. The method does not require a priori knowledge of the binding pose as long as the docking technique used can generate reasonable binding modes. We demonstrate the method on the protein FKBP12 and eight of its inhibitors.

1.
P. A.
Kollman
,
Chem. Rev. (Washington, D.C.)
7
,
2395
(
1993
);
C.
Chipot
and
D. A.
Pearlman
,
Mol. Simul.
28
,
1
(
2002
).
2.
R. W.
Zwanzig
,
J. Chem. Phys.
22
,
1420
(
1954
).
3.
M. R.
Shirts
, Ph.D. dissertation,
Stanford University
,
2005
(ProQuest location: http://wwwlib.umi.com/dissertations/fullcit/3153076).
4.
T.
Hansson
,
C.
Oostenbrink
, and
W. F. v.
Gunsteren
,
Curr. Opin. Struct. Biol.
12
,
190
(
2002
);
[PubMed]
M.
Karplus
and
J. A.
McCammon
,
Nat. Struct. Biol.
9
,
646
(
2002
).
[PubMed]
5.
M.
Souaille
and
B.
Roux
,
Comput. Phys. Commun.
135
,
40
(
2001
);
S.
Kumar
,
D.
Bouzida
,
R. H.
Swendsen
,
P. A.
Kollman
, and
J. M.
Rosenberg
,
J. Comput. Chem.
13
,
1011
(
1992
);
C.
Bartels
,
M.
Schaefer
, and
M.
Karplus
,
J. Chem. Phys.
111
,
8048
(
1999
).
6.
B. D.
Bursulaya
,
M.
Totrov
,
R.
Abagyan
, and
C. L.
Brooks
III
,
J. Comput.-Aided Mol. Des.
17
,
755
(
2003
);
[PubMed]
G. L.
Warren
,
C. W.
Andrews
,
A.-M.
Capelli
 et al,
J. Med. Chem.
(
2005
).
7.
C. H.
Bennett
,
J. Comput. Phys.
22
,
245
(
1976
);
M. R.
Shirts
,
E.
Bair
,
G.
Hooker
, and
V. S.
Pande
,
Phys. Rev. Lett.
91
,
140601
(
2003
).
[PubMed]
8.
M. R.
Shirts
and
V. S.
Pande
,
J. Chem. Phys.
122
,
144107
(
2005
).
9.
M. L.
Lamb
and
W. L.
Jorgensen
,
J. Med. Chem.
41
,
3928
(
1998
);
[PubMed]
M. L.
Lamb
,
J.
Tirado-Rives
, and
W. L.
Jorgensen
,
Bioorg Med. Chem.
7
,
851
(
1999
).
[PubMed]
10.
H.
Fujitani
,
Y.
Tanida
,
M.
Ito
,
G.
Jayachandran
,
C. D.
Snow
,
M. R.
Shirts
,
E. J.
Sorin
, and
V. S.
Pande
,
J. Chem. Phys.
123
,
084108
(
2005
).
11.
D. A.
Holt
,
J. I.
Luengo
,
D. S.
Yamashita
 et al,
J. Am. Chem. Soc.
115
,
9925
(
1993
).
12.
M. R.
Shirts
,
J. W.
Pitera
,
W. C.
Swope
, and
V. S.
Pande
,
J. Chem. Phys.
119
,
5740
(
2003
).
13.
A.
Hodel
,
L. M.
Rice
,
T.
Simonson
,
R. O.
Fox
, and
A. T.
Brunger
,
Protein Sci.
4
,
636
(
1995
);
[PubMed]
M.
Leitgeb
,
C.
Schroder
, and
S.
Boresch
,
J. Chem. Phys.
122
,
84109
(
2005
);
[PubMed]
T. P.
Straatsma
and
J. A.
McCammon
,
J. Chem. Phys.
90
,
3300
(
1988
).
14.
S.
Boresch
,
F.
Tettinger
,
M.
Leitgeb
, and
M.
Karplus
,
J. Phys. Chem. A
107
,
9535
(
2003
).
15.
A. N.
Jain
,
J. Med. Chem.
46
,
499
(
2003
).
16.
M. Y.
Shen
and
K. F.
Freed
,
Proteins
49
,
439
(
2002
).
17.
OpenEye scientific software, OMEGA, http://www.eyesopen.com/products/applications/omega.html
18.
E. J.
Sorin
and
V. S.
Pande
,
J. Comput. Chem.
26
,
682
(
2005
);
[PubMed]
W. D.
Cornell
,
P.
Cieplak
,
C. I.
Barly
,
I. R.
Gould
,
K. M.
Merz
,
D. M.
Ferguson
,
D. C.
Spellmeyer
,
T.
Fox
,
J. W.
Caldwell
, and
P. A.
Kollman
,
J. Am. Chem. Soc.
117
,
5179
(
1995
).
19.
J. M.
Wang
,
R. M.
Wolf
,
J. W.
Caldwell
,
P. A.
Kollman
, and
D. A.
Case
,
J. Comput. Chem.
25
,
1157
(
2004
).
20.
A.
Jakalian
,
D. B.
Jack
, and
C. I.
Bayly
,
J. Comput. Chem.
23
,
1623
(
2002
).
21.
W. L.
Jorgensen
,
J.
Chandrasekhar
,
J. D.
Madura
,
R. W.
Impey
, and
M. L.
Klein
,
J. Chem. Phys.
79
,
926
(
1983
).
22.
M.
Shirts
and
V. S.
Pande
,
Science
290
,
1903
(
2000
);
[PubMed]
23.
E.
Lindahl
,
B.
Hess
, and
D. v. d.
Spoel
,
J. Mol. Model.
7
,
306
(
2001
).
24.
M.
Amini
,
J. W.
Eastwood
, and
R. W.
Hockney
,
Comput. Phys. Commun.
44
,
83
(
1987
).
25.
H. C.
Andersen
,
J. Chem. Phys.
52
,
24
(
1980
).
26.
S.
Nose
and
M. L.
Klein
,
Mol. Phys.
50
,
1055
(
1983
);
M.
Parrinello
and
A.
Rahman
,
J. Appl. Phys.
52
,
7182
(
1981
).
27.
T.
Darden
,
D.
York
, and
L.
Pederson
,
J. Chem. Phys.
98
,
10089
(
1993
).
28.
M. K.
Gilson
,
J. A.
Given
,
B. L.
Bush
, and
J. A.
McCammon
,
Biophys. J.
72
,
1047
(
1997
).
29.
S. J.
Russell
and
P.
Norvig
,
Artificial Intelligence: A Modern Approach
, 2nd ed. (
Prentice-Hall
,
Englewood Cliffs, NJ
,
2002
);
T. M.
Mitchell
,
Machine Learning
(
McGraw-Hill Higher Education
,
New York
,
1997
).
30.
W. C.
Swope
,
J. W.
Pitera
, and
F.
Suits
,
J. Phys. Chem. B
108
,
6571
(
2004
).
31.
N.
Singhal
,
C. D.
Snow
, and
V. S.
Pande
,
J. Chem. Phys.
121
,
415
(
2004
).
32.
D. L.
Mobley
,
J. D.
Chodera
, and
K. A.
Dill
,
J. Chem. Phys.
125
,
084902
(
2006
), following paper.
33.
W. C.
Swope
,
J. W.
Pitera
,
F.
Suits
 et al,
J. Phys. Chem. B
108
,
6582
(
2004
).
34.
G.
Jayachandran
,
V.
Vishal
, and
V. S.
Pande
,
J. Chem. Phys.
124
,
164902
(
2006
).
35.
H.
Fujitani
(private communication).
You do not currently have access to this content.