suppmat954. 3352KB Jun 05 2011 09:30:56 PM
On the transferability of hydration-parametrized continuum
electrostatics models to solvated binding calculations†
Kathryn N. Rankin, Traian Sulea and Enrico O. Purisima∗
Biotechnology Research Institute, National Research Council of Canada,
6100 Royalmount Avenue, Montreal, Quebec H4P 2R2, Canada
Supporting Information
(Table S1, S2 and S3, Figure S1; 12 pages)
∗
†
Corresponding author. Email: rico@bri.nrc.ca
NRCC publication no. 00000
2
Table S1. Experimental hydration free energies11,12 (kcal/mol) and calculated molecular surface
area, MSA (Ų), for the 210 neutral organic small molecules in the dataset.
Molecule
exp
Ghydr
MSAa
0.75
1.20
1.23
1.58
1.60
1.71
1.83
1.96
2.08
2.32
2.33
2.38
2.49
2.50
2.51
2.52
2.59
2.62
2.85
2.88
2.89
134.81
165.36
277.92
215.74
122.21
104.80
229.44
169.94
146.79
97.44
105.01
159.00
169.05
145.22
168.02
138.35
190.57
165.78
181.03
168.77
122.15
-0.18
-0.30
-0.40
-0.44
-0.45
-0.53
-0.80
-0.81
-0.84
-0.86
-0.87
-0.89
-0.90
-2.37
-2.39
-2.47
165.86
176.77
194.46
162.39
201.38
144.37
231.11
125.47
146.85
89.58
133.31
126.06
174.31
161.30
167.59
151.30
Alkanes
cyclopropane
cyclopentane
cyclohexane
cis-12-dimethylcyclohexane
methylcyclopentane
methylcyclohexane
ethane
propane
n-butane
i-butane
n-pentane
i-pentane
n-hexane
neopentane
3-methylpentane
i-hexane
22-dimethylbutane
n-heptane
224-trimethylpentane
24-dimethylpentane
n-octane
Arenes
t-amylbenzene
2-propylbenzene
butylbenzene
t-butylbenzene
2-butylbenzene
propylbenzene
ethylbenzene
p-xylene
m-xylene
124-trimethylbenzene
benzene
toluene
o-xylene
a-methylnaphthalene
naphthalene
13-dimethylnaphthalene
3
Table S1 continued.
26-dimethylnaphthalene
biphenyl
23-dimethylnaphthalene
14-dimethylnaphthalene
acenaphthene
fluorene
phenanthrene
anthracene
pyrene
-2.63
-2.64
-2.78
-2.82
-3.15
-3.44
-3.95
-4.23
-4.46
173.93
156.78
133.06
172.50
152.21
250.64
197.41
163.29
146.50
-3.74
-3.89
-3.91
-3.93
-3.93
-4.01
-4.08
-4.10
-4.25
-4.35
-4.36
-4.39
-4.42
-4.42
-4.43
-4.47
-4.51
-4.52
-4.58
-4.72
-4.76
-4.83
-5.01
-5.12
-5.48
-5.49
-5.49
-5.49
-5.87
-5.92
-6.14
-6.62
159.23
233.73
97.41
217.29
218.50
168.38
149.26
146.40
138.99
130.42
126.29
134.95
149.61
214.40
217.00
164.88
141.41
220.27
189.43
212.52
157.59
158.20
168.21
185.82
149.09
168.94
237.38
156.99
200.10
141.39
93.38
124.47
Alcohols
4-methyl-2-pentanol
2-methyl-3-pentanol
23-dimethyl-2-butanol
2-methyl-2-pentanol
2-methyl-1-pentanol
4-heptanol
3-hexanol
1-octanol
1-heptanol
3-pentanol
1-hexanol
2-pentanol
3-methyl-1-butanol
2-methyl-1-butanol
2-methyl-2-butanol
1-pentanol
t-butanol
2-methyl-1-propanol
2-butanol
1-butanol
2-propanol
1-propanol
ethanol
methanol
cyclohexanol
3-methylphenol
cycloheptanol
cyclopentanol
2-methylphenol
4-t-butylphenol
4-methylphenol
phenol
4
Table S1 continued.
Ethers
di-n-butylether
di-n-propylether
di-i-propylether
diethylether
methyl-n-propylether
ethyl-n-propylether
dimethylether
methyl-i-propylether
methyl-t-butylether
methyl-phenylether
25-dimethyltetrahydrofuran
tetrahydropyran
2-methyltetrahydrofuran
tetrahydrofuran
ethyl-phenylether
-0.83
-1.15
-0.53
-1.64
-1.66
-1.81
-1.90
-2.01
-2.21
-2.45
-2.92
-3.12
-3.30
-3.47
-4.28
188.16
208.77
156.09
116.07
141.53
209.93
146.92
158.51
137.75
118.91
153.61
192.55
113.84
195.60
209.35
-2.15
-2.48
-2.67
-2.74
-2.88
-2.89
-2.93
-3.04
-3.06
-3.24
-3.29
-3.41
-3.53
-3.64
-3.85
-4.58
-4.68
176.21
115.61
137.71
150.81
136.12
196.23
137.33
191.43
160.14
160.75
210.34
137.99
156.13
217.12
227.79
165.94
186.35
Carboxylic Acids
-6.16
-6.21
-6.36
-6.48
-6.70
147.01
245.24
195.66
123.91
178.75
Ketones
2-undecanone
2-nonanone
5-nonanone
24-dimethyl-3-pentanone
2-octanone
33-dimethylbutanone
4-heptanone
2-heptanone
4-methyl-2-pentanone
3-methyl-2-butanone
2-hexanone
3-pentanone
2-pentanone
2-butanone
acetone
acetophenone
cyclopentanone
pentanoic acid
hexanoic acid
butyric acid
propionic acid
acetic acid
5
Table S1 continued.
ethylheptanoate
i-butylacetate
amylacetate
n-propylpropionate
methylhexanoate
ethylbutanoate
ethylpentanoate
butylacetate
methylpentanoate
i-propylacetate
ethylpropionate
methylbutanoate
n-propylacetate
methylpropionate
ethylacetate
methylacetate
methylbenzoate
-2.30
-2.36
-2.45
-2.46
-2.48
-2.50
-2.52
-2.55
-2.57
-2.65
-2.80
-2.83
-2.86
-2.93
-3.10
-3.32
-4.28
187.07
116.08
185.70
126.51
140.09
161.29
183.56
174.45
98.50
180.56
203.58
80.02
129.68
122.11
191.07
229.94
167.42
-2.90
-3.02
-3.24
-3.33
-3.66
-3.89
-3.98
-4.03
-4.07
-4.10
-4.29
-4.30
-4.39
-4.50
-4.56
-5.11
-5.41
-5.48
-5.49
-5.56
78.54
152.49
39.24
168.73
185.30
169.73
163.06
164.67
170.30
153.25
178.36
165.90
194.48
184.61
115.12
147.15
111.54
144.57
141.55
140.13
Amines
NN-dimethylaniline
triethylamine
trimethylamine
di-n-butylamine
di-n-propylamine
N-methylpiperidine
N-methylpyrrolidine
n-hexylamine
diethylamine
n-pentylamine
dimethylamine
n-butylamine
n-propylamine
ethylamine
methylamine
piperidine
aziridine
pyrrolidine
aniline
azetidine
6
Table S1 continued.
Amides
NN-dimethylacetamide
propionamide
acetamide
cis-N-methylacetamide
N-methylacetamide
2-ethylpyridine
26-dimethylpyridine
3-ethylpyridine
2-methylpyridine
pyridine
25-dimethylpyridine
4-ethylpyridine
3-methylpyridine
23-dimethylpyridine
35-dimethylpyridine
24-dimethylpyridine
4-methylpyridine
34-dimethylpyridine
3-methylindole
-8.50
-9.41
-9.71
-10.10
-10.10
180.38
190.58
184.59
236.12
167.56
N-Heteroarenes
-4.33
-4.60
-4.60
-4.63
-4.70
-4.70
-4.72
-4.77
-4.83
-4.84
-4.85
-4.92
-5.21
-5.91
175.73
195.56
130.86
94.91
126.69
131.89
156.57
169.63
150.86
216.33
178.86
143.09
196.51
169.11
Sulfur-containing Compounds
1-propanethiol
-1.05
methanethiol
-1.24
dipropylsulfide
-1.27
ethanethiol
-1.30
diethylsulfide
-1.43
methyl-ethylsulfide
-1.49
dimethylsulfide
-1.54
diethyldisulfide
-1.63
dimethyldisulfide
-1.83
benzenethiol
-2.55
methyl-phenylsulfide
-2.73
163.17
144.58
204.57
142.43
137.23
142.51
162.58
95.77
120.09
152.17
122.11
Poly-functional Compounds
12-diethoxyethane
-3.53
2-i-butyl-3-methoxypyrazine
-3.68
2-ethyl-3-methoxypyrazine
-4.39
12-dimethoxyethane
-4.84
2-i-butylpyrazine
-5.05
110.73
175.57
170.07
130.73
193.22
7
Table S1 continued.
14-dioxane
-5.06
2-ethylpyrazine
-5.46
2-methylpyrazine
-5.52
2-butoxyethanol
-6.27
tip3p
-6.30
4-methylmorpholine
-6.34
2-propoxyethanol
-6.42
2-methoxyethanamine
-6.55
2-ethoxyethanol
-6.61
2-methoxyethanol
-6.77
3-methoxy-1-propanamine
-6.93
morpholine
-7.18
piperazine
-7.38
NN-dimethylpiperazine
-7.58
N-methylpiperazine
-7.78
4-methylimidazole
-10.25
n-propylguanidine
-10.92
a
The molecular surface area was calculated using
AMBER van der Waals radii.17
193.66
176.55
70.49
206.98
225.34
205.24
153.56
214.24
216.08
212.44
146.47
123.65
122.51
103.22
168.26
159.38
149.09
the SIMS molecular surface program21 and
8
Table S2. Effect of ( ρ , Din ) parameter sets on the calculated electrostatic hydration free energy
(kcal/mol) for the series of benzamidine analogs.
H2N
+
NH2
H2N
H2N
NH2
O
H2N
null
(I)
(II)
+
NH2
OH
(III)
+
H2N
O
-
NH2
O
(IV)
(V)
(VI)
G1R→78.5
( ρ , Din )
I
II
III
IV
V
VI
(1.100,1.0)
-56.25
0.00
-9.75
-59.63
-49.31
-2.03
(1.075,1.2)
-56.62
0.00
-9.76
-60.08
-49.13
-2.02
(1.050,1.4)
-57.81
0.00
-9.86
-60.35
-48.58
-1.98
(1.025,1.6)
-57.33
0.00
-9.81
-60.75
-48.67
-2.00
(1.000,1.8)
-57.95
0.00
-9.74
-60.74
-46.82
-2.02
(0.975,2.0)
-57.94
0.00
-10.10
-61.37
-47.40
-2.09
(0.950,2.2)
-58.03
0.00
-9.94
-61.07
-48.31
-2.08
(0.925,2.4)
-58.54
0.00
-10.05
-61.32
-48.66
-2.16
(0.900,2.8)
-58.53
0.00
-9.72
-61.12
-48.59
-2.14
(0.875,3.2)
-58.47
0.00
-9.69
-60.81
-47.78
-2.17
9
Table S3. Effect of ρ on the calculated absolute (∆A (Å2)) change in molecular surface area
upon binding benzamidine to trypsin and the calculated relativea (∆∆A (Å2)) change in molecular
surface area upon binding for a series of benzamidine analogs to trypsin.b
H2N
+
NH2
NH2
H2N
H2N
O
null
(I)
ρ
H2N
+
NH2
OH
(II)
(III)
∆A (Å2)
(IV)
+
H2N
O
NH2
-O
(V)
(VI)
∆∆A (Å2)
I
II
III
IV
V
VI
1.100
-269.13
0.00
2.46
-10.37
-23.10
32.59
1.075
-273.57
0.00
-0.72
-13.88
-27.90
30.37
1.050
-273.32
0.00
1.14
-11.73
-26.07
30.94
1.025
-269.99
0.00
2.25
-8.67
-25.83
31.60
1.000
-275.29
0.00
2.14
-7.68
-21.79
30.95
0.975
-269.50
0.00
2.17
-10.16
-24.43
34.34
0.950
269.83
0.00
2.58
-8.54
-23.29
31.30
0.925
-266.95
0.00
1.71
-10.29
-22.24
30.82
0.900
-265.24
0.00
-1.33
-12.51
-24.60
27.99
0.875
-265.45
0.00
1.89
-10.09
-20.76
30.50
a
Benzamidine (I) is taken as the reference.
b
The largest variation in the relative non-polar term upon binding to trypsin (Eq (2)) is observed
for analog VI and is 0.127 kcal/mol at α = 0.020 kcal/(mol.Å2). Note that the non-polar term
variation is due to the scaling of the atomic radii.
10
Figure Captions
Figure S1. Dependence of the components of the calculated absolute electrostatic free energy of
binding between trypsin and benzamidine on AMBER atomic radii linear scaling factor ρ, and
solute interior dielectric constant, Din. 3D-surface representation of (a) Coulomb interaction
energy; (b) change in reaction field energy; (c) reaction field energy of tryspsin-benzamidine
complex; (d) reaction field energy of benzamidine; (e) reaction field energy of trypsin.
11
(a)
30
Ecoul (kcal/mol)
25
20
15
10
5
0
0.850.900
0
0.950.000
1
1.050 00
1.1
ρ
4.5 5.0
3.5 4.0
2.5 3.0
2.0
1.0 1.5
Din
(b)
0
∆GR
bind (kcal/mol)
-10
-20
-30
-40
-50
-60
0.850.900
0
0.950.000
1
1.050 00
1.1
ρ
3.0 3.5
2.0 2.5
1.0 1.5
in
5.0
4.0 4.5
D
(c)
0
R
Gcomplex
(kcal/mol)
-500
-1000
-1500
-2000
-2500
-3000
0.8500.900
0.950.000
1
1.050 00
1.1
ρ
Figure S1.
4.0
3.0 3.5
2.0 2.5
1.0 1.5
Din
4.5 5.0
12
(d)
R
Gbenzamidine
(kcal/mol)
0
-10
-20
-30
-40
-50
-60
-70
-80
0.8500.900
0.950.000
1
1.050 00
1.1
ρ
3.0 3.5
2.0 2.5
1.0 1.5
Din
4.0 4.5
5.0
(e)
0
R
Gtrypsin (kcal/mol)
-500
-1000
-1500
-2000
-2500
-3000
0.8500.900
0.950.000
1
1.050 00
1.1
ρ
3.0 3.5
2.0 2.5
1.0 1.5
Din
Figure S1 continued.
4.0 4.5
5.0
electrostatics models to solvated binding calculations†
Kathryn N. Rankin, Traian Sulea and Enrico O. Purisima∗
Biotechnology Research Institute, National Research Council of Canada,
6100 Royalmount Avenue, Montreal, Quebec H4P 2R2, Canada
Supporting Information
(Table S1, S2 and S3, Figure S1; 12 pages)
∗
†
Corresponding author. Email: rico@bri.nrc.ca
NRCC publication no. 00000
2
Table S1. Experimental hydration free energies11,12 (kcal/mol) and calculated molecular surface
area, MSA (Ų), for the 210 neutral organic small molecules in the dataset.
Molecule
exp
Ghydr
MSAa
0.75
1.20
1.23
1.58
1.60
1.71
1.83
1.96
2.08
2.32
2.33
2.38
2.49
2.50
2.51
2.52
2.59
2.62
2.85
2.88
2.89
134.81
165.36
277.92
215.74
122.21
104.80
229.44
169.94
146.79
97.44
105.01
159.00
169.05
145.22
168.02
138.35
190.57
165.78
181.03
168.77
122.15
-0.18
-0.30
-0.40
-0.44
-0.45
-0.53
-0.80
-0.81
-0.84
-0.86
-0.87
-0.89
-0.90
-2.37
-2.39
-2.47
165.86
176.77
194.46
162.39
201.38
144.37
231.11
125.47
146.85
89.58
133.31
126.06
174.31
161.30
167.59
151.30
Alkanes
cyclopropane
cyclopentane
cyclohexane
cis-12-dimethylcyclohexane
methylcyclopentane
methylcyclohexane
ethane
propane
n-butane
i-butane
n-pentane
i-pentane
n-hexane
neopentane
3-methylpentane
i-hexane
22-dimethylbutane
n-heptane
224-trimethylpentane
24-dimethylpentane
n-octane
Arenes
t-amylbenzene
2-propylbenzene
butylbenzene
t-butylbenzene
2-butylbenzene
propylbenzene
ethylbenzene
p-xylene
m-xylene
124-trimethylbenzene
benzene
toluene
o-xylene
a-methylnaphthalene
naphthalene
13-dimethylnaphthalene
3
Table S1 continued.
26-dimethylnaphthalene
biphenyl
23-dimethylnaphthalene
14-dimethylnaphthalene
acenaphthene
fluorene
phenanthrene
anthracene
pyrene
-2.63
-2.64
-2.78
-2.82
-3.15
-3.44
-3.95
-4.23
-4.46
173.93
156.78
133.06
172.50
152.21
250.64
197.41
163.29
146.50
-3.74
-3.89
-3.91
-3.93
-3.93
-4.01
-4.08
-4.10
-4.25
-4.35
-4.36
-4.39
-4.42
-4.42
-4.43
-4.47
-4.51
-4.52
-4.58
-4.72
-4.76
-4.83
-5.01
-5.12
-5.48
-5.49
-5.49
-5.49
-5.87
-5.92
-6.14
-6.62
159.23
233.73
97.41
217.29
218.50
168.38
149.26
146.40
138.99
130.42
126.29
134.95
149.61
214.40
217.00
164.88
141.41
220.27
189.43
212.52
157.59
158.20
168.21
185.82
149.09
168.94
237.38
156.99
200.10
141.39
93.38
124.47
Alcohols
4-methyl-2-pentanol
2-methyl-3-pentanol
23-dimethyl-2-butanol
2-methyl-2-pentanol
2-methyl-1-pentanol
4-heptanol
3-hexanol
1-octanol
1-heptanol
3-pentanol
1-hexanol
2-pentanol
3-methyl-1-butanol
2-methyl-1-butanol
2-methyl-2-butanol
1-pentanol
t-butanol
2-methyl-1-propanol
2-butanol
1-butanol
2-propanol
1-propanol
ethanol
methanol
cyclohexanol
3-methylphenol
cycloheptanol
cyclopentanol
2-methylphenol
4-t-butylphenol
4-methylphenol
phenol
4
Table S1 continued.
Ethers
di-n-butylether
di-n-propylether
di-i-propylether
diethylether
methyl-n-propylether
ethyl-n-propylether
dimethylether
methyl-i-propylether
methyl-t-butylether
methyl-phenylether
25-dimethyltetrahydrofuran
tetrahydropyran
2-methyltetrahydrofuran
tetrahydrofuran
ethyl-phenylether
-0.83
-1.15
-0.53
-1.64
-1.66
-1.81
-1.90
-2.01
-2.21
-2.45
-2.92
-3.12
-3.30
-3.47
-4.28
188.16
208.77
156.09
116.07
141.53
209.93
146.92
158.51
137.75
118.91
153.61
192.55
113.84
195.60
209.35
-2.15
-2.48
-2.67
-2.74
-2.88
-2.89
-2.93
-3.04
-3.06
-3.24
-3.29
-3.41
-3.53
-3.64
-3.85
-4.58
-4.68
176.21
115.61
137.71
150.81
136.12
196.23
137.33
191.43
160.14
160.75
210.34
137.99
156.13
217.12
227.79
165.94
186.35
Carboxylic Acids
-6.16
-6.21
-6.36
-6.48
-6.70
147.01
245.24
195.66
123.91
178.75
Ketones
2-undecanone
2-nonanone
5-nonanone
24-dimethyl-3-pentanone
2-octanone
33-dimethylbutanone
4-heptanone
2-heptanone
4-methyl-2-pentanone
3-methyl-2-butanone
2-hexanone
3-pentanone
2-pentanone
2-butanone
acetone
acetophenone
cyclopentanone
pentanoic acid
hexanoic acid
butyric acid
propionic acid
acetic acid
5
Table S1 continued.
ethylheptanoate
i-butylacetate
amylacetate
n-propylpropionate
methylhexanoate
ethylbutanoate
ethylpentanoate
butylacetate
methylpentanoate
i-propylacetate
ethylpropionate
methylbutanoate
n-propylacetate
methylpropionate
ethylacetate
methylacetate
methylbenzoate
-2.30
-2.36
-2.45
-2.46
-2.48
-2.50
-2.52
-2.55
-2.57
-2.65
-2.80
-2.83
-2.86
-2.93
-3.10
-3.32
-4.28
187.07
116.08
185.70
126.51
140.09
161.29
183.56
174.45
98.50
180.56
203.58
80.02
129.68
122.11
191.07
229.94
167.42
-2.90
-3.02
-3.24
-3.33
-3.66
-3.89
-3.98
-4.03
-4.07
-4.10
-4.29
-4.30
-4.39
-4.50
-4.56
-5.11
-5.41
-5.48
-5.49
-5.56
78.54
152.49
39.24
168.73
185.30
169.73
163.06
164.67
170.30
153.25
178.36
165.90
194.48
184.61
115.12
147.15
111.54
144.57
141.55
140.13
Amines
NN-dimethylaniline
triethylamine
trimethylamine
di-n-butylamine
di-n-propylamine
N-methylpiperidine
N-methylpyrrolidine
n-hexylamine
diethylamine
n-pentylamine
dimethylamine
n-butylamine
n-propylamine
ethylamine
methylamine
piperidine
aziridine
pyrrolidine
aniline
azetidine
6
Table S1 continued.
Amides
NN-dimethylacetamide
propionamide
acetamide
cis-N-methylacetamide
N-methylacetamide
2-ethylpyridine
26-dimethylpyridine
3-ethylpyridine
2-methylpyridine
pyridine
25-dimethylpyridine
4-ethylpyridine
3-methylpyridine
23-dimethylpyridine
35-dimethylpyridine
24-dimethylpyridine
4-methylpyridine
34-dimethylpyridine
3-methylindole
-8.50
-9.41
-9.71
-10.10
-10.10
180.38
190.58
184.59
236.12
167.56
N-Heteroarenes
-4.33
-4.60
-4.60
-4.63
-4.70
-4.70
-4.72
-4.77
-4.83
-4.84
-4.85
-4.92
-5.21
-5.91
175.73
195.56
130.86
94.91
126.69
131.89
156.57
169.63
150.86
216.33
178.86
143.09
196.51
169.11
Sulfur-containing Compounds
1-propanethiol
-1.05
methanethiol
-1.24
dipropylsulfide
-1.27
ethanethiol
-1.30
diethylsulfide
-1.43
methyl-ethylsulfide
-1.49
dimethylsulfide
-1.54
diethyldisulfide
-1.63
dimethyldisulfide
-1.83
benzenethiol
-2.55
methyl-phenylsulfide
-2.73
163.17
144.58
204.57
142.43
137.23
142.51
162.58
95.77
120.09
152.17
122.11
Poly-functional Compounds
12-diethoxyethane
-3.53
2-i-butyl-3-methoxypyrazine
-3.68
2-ethyl-3-methoxypyrazine
-4.39
12-dimethoxyethane
-4.84
2-i-butylpyrazine
-5.05
110.73
175.57
170.07
130.73
193.22
7
Table S1 continued.
14-dioxane
-5.06
2-ethylpyrazine
-5.46
2-methylpyrazine
-5.52
2-butoxyethanol
-6.27
tip3p
-6.30
4-methylmorpholine
-6.34
2-propoxyethanol
-6.42
2-methoxyethanamine
-6.55
2-ethoxyethanol
-6.61
2-methoxyethanol
-6.77
3-methoxy-1-propanamine
-6.93
morpholine
-7.18
piperazine
-7.38
NN-dimethylpiperazine
-7.58
N-methylpiperazine
-7.78
4-methylimidazole
-10.25
n-propylguanidine
-10.92
a
The molecular surface area was calculated using
AMBER van der Waals radii.17
193.66
176.55
70.49
206.98
225.34
205.24
153.56
214.24
216.08
212.44
146.47
123.65
122.51
103.22
168.26
159.38
149.09
the SIMS molecular surface program21 and
8
Table S2. Effect of ( ρ , Din ) parameter sets on the calculated electrostatic hydration free energy
(kcal/mol) for the series of benzamidine analogs.
H2N
+
NH2
H2N
H2N
NH2
O
H2N
null
(I)
(II)
+
NH2
OH
(III)
+
H2N
O
-
NH2
O
(IV)
(V)
(VI)
G1R→78.5
( ρ , Din )
I
II
III
IV
V
VI
(1.100,1.0)
-56.25
0.00
-9.75
-59.63
-49.31
-2.03
(1.075,1.2)
-56.62
0.00
-9.76
-60.08
-49.13
-2.02
(1.050,1.4)
-57.81
0.00
-9.86
-60.35
-48.58
-1.98
(1.025,1.6)
-57.33
0.00
-9.81
-60.75
-48.67
-2.00
(1.000,1.8)
-57.95
0.00
-9.74
-60.74
-46.82
-2.02
(0.975,2.0)
-57.94
0.00
-10.10
-61.37
-47.40
-2.09
(0.950,2.2)
-58.03
0.00
-9.94
-61.07
-48.31
-2.08
(0.925,2.4)
-58.54
0.00
-10.05
-61.32
-48.66
-2.16
(0.900,2.8)
-58.53
0.00
-9.72
-61.12
-48.59
-2.14
(0.875,3.2)
-58.47
0.00
-9.69
-60.81
-47.78
-2.17
9
Table S3. Effect of ρ on the calculated absolute (∆A (Å2)) change in molecular surface area
upon binding benzamidine to trypsin and the calculated relativea (∆∆A (Å2)) change in molecular
surface area upon binding for a series of benzamidine analogs to trypsin.b
H2N
+
NH2
NH2
H2N
H2N
O
null
(I)
ρ
H2N
+
NH2
OH
(II)
(III)
∆A (Å2)
(IV)
+
H2N
O
NH2
-O
(V)
(VI)
∆∆A (Å2)
I
II
III
IV
V
VI
1.100
-269.13
0.00
2.46
-10.37
-23.10
32.59
1.075
-273.57
0.00
-0.72
-13.88
-27.90
30.37
1.050
-273.32
0.00
1.14
-11.73
-26.07
30.94
1.025
-269.99
0.00
2.25
-8.67
-25.83
31.60
1.000
-275.29
0.00
2.14
-7.68
-21.79
30.95
0.975
-269.50
0.00
2.17
-10.16
-24.43
34.34
0.950
269.83
0.00
2.58
-8.54
-23.29
31.30
0.925
-266.95
0.00
1.71
-10.29
-22.24
30.82
0.900
-265.24
0.00
-1.33
-12.51
-24.60
27.99
0.875
-265.45
0.00
1.89
-10.09
-20.76
30.50
a
Benzamidine (I) is taken as the reference.
b
The largest variation in the relative non-polar term upon binding to trypsin (Eq (2)) is observed
for analog VI and is 0.127 kcal/mol at α = 0.020 kcal/(mol.Å2). Note that the non-polar term
variation is due to the scaling of the atomic radii.
10
Figure Captions
Figure S1. Dependence of the components of the calculated absolute electrostatic free energy of
binding between trypsin and benzamidine on AMBER atomic radii linear scaling factor ρ, and
solute interior dielectric constant, Din. 3D-surface representation of (a) Coulomb interaction
energy; (b) change in reaction field energy; (c) reaction field energy of tryspsin-benzamidine
complex; (d) reaction field energy of benzamidine; (e) reaction field energy of trypsin.
11
(a)
30
Ecoul (kcal/mol)
25
20
15
10
5
0
0.850.900
0
0.950.000
1
1.050 00
1.1
ρ
4.5 5.0
3.5 4.0
2.5 3.0
2.0
1.0 1.5
Din
(b)
0
∆GR
bind (kcal/mol)
-10
-20
-30
-40
-50
-60
0.850.900
0
0.950.000
1
1.050 00
1.1
ρ
3.0 3.5
2.0 2.5
1.0 1.5
in
5.0
4.0 4.5
D
(c)
0
R
Gcomplex
(kcal/mol)
-500
-1000
-1500
-2000
-2500
-3000
0.8500.900
0.950.000
1
1.050 00
1.1
ρ
Figure S1.
4.0
3.0 3.5
2.0 2.5
1.0 1.5
Din
4.5 5.0
12
(d)
R
Gbenzamidine
(kcal/mol)
0
-10
-20
-30
-40
-50
-60
-70
-80
0.8500.900
0.950.000
1
1.050 00
1.1
ρ
3.0 3.5
2.0 2.5
1.0 1.5
Din
4.0 4.5
5.0
(e)
0
R
Gtrypsin (kcal/mol)
-500
-1000
-1500
-2000
-2500
-3000
0.8500.900
0.950.000
1
1.050 00
1.1
ρ
3.0 3.5
2.0 2.5
1.0 1.5
Din
Figure S1 continued.
4.0 4.5
5.0