The interactions of the polar chemical bonds such as C=O and N–H with an external electric field were investigated, and a linear relationship between the QM/MM interaction energies and the electric field along the chemical bond is established in the range of weak to intermediate electrical fields. The linear relationship indicates that the electrostatic interactions of a polar group with its surroundings can be described by a simple model of a dipole with constant moment under the action of an electric field. This relationship is employed to develop a general approach to generating an electrostatic energy-based charge (EEC) model for molecules containing single or multiple polar chemical bonds. Benchmark test studies of this model were carried out for (CH3)2–CO and N-methyl acetamide in explicit water, and the result shows that the EEC model gives more accurate electrostatic energies than those given by the widely used charge model based on fitting to the electrostatic potential (ESP) in direct comparison to the energies computed by the QM/MM method. The MD simulations of the electric field at the active site of ketosteroid isomerase based on EEC demonstrated that EEC gave a better representation of the electrostatic interaction in the hydrogen-bonding environment than the Amber14SB force field by comparison with experiment. The current study suggests that EEC should be better suited for molecular dynamics study of molecular systems with polar chemical bonds such as biomolecules than the widely used ESP or RESP (restrained ESP) charge models.

1.
N.
Foloppe
and
A. D.
MacKerell
, Jr.
,
J. Phys. Chem. B
102
,
6669
(
1998
).
2.
N.
Foloppe
and
A. D.
MacKerell
, Jr.
,
J. Comput. Chem.
21
,
86
(
2000
).
3.
A. D.
MacKerell
, Jr.
and
N. K.
Banavali
,
J. Comput. Chem.
21
,
105
(
2000
).
4.
J. B.
Klauda
 et al,
J. Phys. Chem. B
114
,
7830
(
2010
).
5.
D. A.
Case
 et al,
J. Comput. Chem.
26
,
1668
(
2005
).
6.
J.
Wang
,
P.
Cieplak
, and
P. A.
Kollman
,
J. Comput. Chem.
21
,
1049
(
2000
).
7.
J.
Wang
 et al,
J. Comput. Chem.
25
,
1157
(
2004
).
8.
W. R. P.
Scott
 et al,
J. Phys. Chem. A
103
,
3596
(
1999
).
9.
W. L.
Jorgensen
,
D. S.
Maxwell
, and
J.
Tirado-Rives
,
J. Am. Chem. Soc.
118
,
11225
(
1996
).
10.
F. A.
Momany
,
J. Phys. Chem.
82
,
592
(
1978
).
11.
U. C.
Singh
and
P. A.
Kollman
,
J. Comput. Chem.
5
,
129
(
1984
).
12.
S. R.
Cox
and
D. E.
Williams
,
J. Comput. Chem.
2
,
304
(
1981
).
13.
P.
Ren
and
J. W.
Ponder
,
J. Phys. Chem. B
107
,
5933
(
2003
).
14.
W.
Xie
 et al,
J. Chem. Theory Comput.
3
,
1878
(
2007
).
15.
J. W.
Ponder
 et al,
J. Phys. Chem. B
114
,
2549
(
2010
).
16.
R.
Kumar
 et al,
J. Chem. Phys.
132
,
014309
(
2010
).
17.
P.
Ren
,
C.
Wu
, and
J. W.
Ponder
,
J. Chem. Theory Comput.
7
,
3143
(
2011
).
18.
M. S.
Gordon
 et al,
Chem. Rev.
112
,
632
(
2012
).
19.
L.-P.
Wang
 et al,
J. Phys. Chem. B
117
,
9956
(
2013
).
20.
A.
Albaugh
 et al,
J. Phys. Chem. B
120
,
9811
(
2016
).
21.
Z. E.
Hughes
 et al,
J. Comput. Chem.
41
,
619
(
2020
).
22.
S.
Cardamone
,
T. J.
Hughes
, and
P. L. A.
Popelier
,
Phys. Chem. Chem. Phys.
16
,
10367
(
2014
).
23.
N.
Plattner
and
M.
Meuwly
,
J. Mol. Model.
15
,
687
(
2009
).
24.
N.
Plattner
and
M.
Meuwly
,
Biophys. J.
94
,
2505
(
2008
).
25.
R. J.
Wheatley
and
S. L.
Price
,
Mol. Phys.
71
,
1381
(
1990
).
26.
A. J.
Stone
,
Chem. Phys. Lett.
83
,
233
(
1981
).
27.
A. J.
Stone
and
M.
Alderton
,
Mol. Phys.
100
,
221
(
2002
).
28.
G.
Lamoureux
,
A. D.
MacKerell
, and
B.
Roux
,
J. Chem. Phys.
119
,
5185
(
2003
).
29.
W.
Yu
 et al,
J. Chem. Phys.
138
,
034508
(
2013
).
30.
O. M.
Szklarczyk
,
S. J.
Bachmann
, and
W. F.
van Gunsteren
,
J. Comput. Chem.
35
,
789
(
2014
).
31.
A.
Savelyev
and
A. D.
MacKerell
, Jr.
,
J. Phys. Chem. B
118
,
6742
(
2014
).
32.
J. A.
Lemkul
 et al,
Chem. Rev.
116
,
4983
(
2016
).
33.
W. J.
Mortier
,
K.
Van Genechten
, and
J.
Gasteiger
,
J. Am. Chem. Soc.
107
,
829
(
1985
).
34.
A. K.
Rappe
and
W. A.
Goddard
 III
,
J. Phys. Chem.
95
,
3358
(
1991
).
35.
S. W.
Rick
,
S. J.
Stuart
, and
B. J.
Berne
,
J. Chem. Phys.
101
,
6141
(
1994
).
36.
C.
Bret
,
M. J.
Field
, and
L.
Hemmingsen
,
Mol. Phys.
98
,
751
(
2000
).
37.
R.
Chelli
and
P.
Procacci
,
J. Chem. Phys.
117
,
9175
(
2002
).
38.
S.
Patel
and
C. L.
Brooks
,
J. Comput. Chem.
25
,
1
(
2004
).
39.
S.
Patel
,
A. D.
Mackerell
, and
C. L.
Brooks
,
J. Comput. Chem.
25
,
1504
(
2004
).
40.
J.
Chen
and
T. J.
Martínez
,
Chem. Phys. Lett.
438
,
315
(
2007
).
41.
Y.
Zhong
and
S.
Patel
,
J. Phys. Chem. B
114
,
11076
(
2010
).
42.
A. J.
Lee
and
S. W.
Rick
,
J. Chem. Phys.
134
,
184507
(
2011
).
43.
C.
Ji
,
Y.
Mei
, and
J. Z. H.
Zhang
,
Biophys. J.
95
,
1080
(
2008
).
44.
C. G.
Ji
and
J. Z. H.
Zhang
,
J. Am. Chem. Soc.
130
,
17129
(
2008
).
45.
Y.
Tong
 et al,
J. Am. Chem. Soc.
131
,
8636
(
2009
).
46.
L. L.
Duan
 et al,
J. Am. Chem. Soc.
132
(
32
),
11159
(
2010
).
47.
X.
Wang
,
X.
He
, and
J. Z. H.
Zhang
,
J. Phys. Chem. A
117
,
6015
(
2013
).
48.
X.
Xiao
 et al,
J. Phys. Chem. B
117
,
14885
(
2013
).
49.
L.
Duan
 et al,
Phys. Chem. Chem. Phys.
19
,
15273
(
2017
).
50.
C.
Ji
and
Y.
Mei
,
Acc. Chem. Res.
47
,
2795
(
2014
).
51.
W. D.
Cornell
 et al,
J. Am. Chem. Soc.
117
,
5179
(
1995
).
52.
C. I.
Bayly
 et al,
J. Phys. Chem.
97
,
10269
(
1993
).
53.
K.
Vanommeslaeghe
 et al,
J. Comput. Chem.
31
,
671
(
2010
).
54.
M.
Saggu
,
N. M.
Levinson
, and
S. G.
Boxer
,
J. Am. Chem. Soc.
133
,
17414
(
2011
).
55.
M.
Saggu
,
N. M.
Levinson
, and
S. G.
Boxer
,
J. Am. Chem. Soc.
134
,
18986
(
2012
).
56.
S. D.
Fried
,
S.
Bagchi
, and
S. G.
Boxer
,
Science
346
,
1510
(
2014
).
57.
S. D.
Fried
and
S. G.
Boxer
,
Annu. Rev. Biochem.
86
,
387
(
2017
).
58.
X.
Wang
and
X.
He
,
Molecules
23
,
2410
(
2018
).
59.
L.
Wang
,
S. D.
Fried
, and
T. E.
Markland
,
J. Phys. Chem. B
121
,
9807
(
2017
).
60.
X.
Wang
,
C.
Lu
, and
M.
Yang
,
Sci. Rep.
10
,
8539
(
2020
).
61.
J. E.
Straub
and
M.
Karplus
,
Chem. Phys.
158
,
221
(
1991
).
62.
D. R.
Nutt
and
M.
Meuwly
,
Biophys. J.
85
,
3612
(
2003
).
63.
D.
Bakowies
and
W.
Thiel
,
J. Phys. Chem.
100
,
10580
(
1996
).
64.
W. L.
Jorgensen
 et al,
J. Chem. Phys.
79
,
926
(
1983
).
66.
A.
Jakalian
,
D. B.
Jack
, and
C. I.
Bayly
,
J. Comput. Chem.
23
,
1623
(
2002
).
67.
J.-P.
Ryckaert
,
G.
Ciccotti
, and
H. J. C.
Berendsen
,
J. Comput. Phys.
23
,
327
(
1977
).
68.
T.
Darden
,
D.
York
, and
L.
Pedersen
,
J. Chem. Phys.
98
,
10089
(
1993
).
69.
R. W.
Pastor
,
B. R.
Brooks
, and
A.
Szabo
,
Mol. Phys.
65
,
1409
(
1988
).
70.
C. A.
Reynolds
,
J. W.
Essex
, and
W. G.
Richards
,
Chem. Phys. Lett.
199
,
257
(
1992
).
71.
T. R.
Stouch
and
D. E.
Williams
,
J. Comput. Chem.
14
,
858
(
1993
).
72.
Y.
Wu
and
S. G.
Boxer
,
J. Am. Chem. Soc.
138
,
11890
(
2016
).
73.
W. L.
DeLano
, The PyMOL molecular graphics system, version 1.5.0.1,
DeLano Scientific
,
San Carlos, CA
,
2012
.
74.
J. A.
Maier
 et al,
J. Chem. Theory Comput.
11
,
3696
(
2015
).
75.
X.
He
 et al,
J. Chem. Phys.
153
,
114502
(
2020
).
76.
S. D.
Fried
and
S. G.
Boxer
,
Acc. Chem. Res.
48
,
998
(
2015
).
77.
S. A.
Corcelli
,
C. P.
Lawrence
, and
J. L.
Skinner
,
J. Chem. Phys.
120
,
8107
(
2004
).
78.
T.
la Cour Jansen
and
J.
Knoester
,
J. Chem. Phys.
124
,
044502
(
2006
).
79.
J.-H.
Choi
 et al,
J. Chem. Phys.
128
,
134506
(
2008
).
80.
J.-H.
Choi
and
M.
Cho
,
J. Chem. Phys.
134
,
154513
(
2011
).

Supplementary Material

You do not currently have access to this content.