Table S1
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: [email protected] 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
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: [email protected] 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
