Supplementary Material Automatic Parametrization of Non-Polar Implicit Solvent Models for the Blind Prediction of Solvation Free Energies

Home , Ethyl pentanoate, Methoxypropane, Methylsulfonylmethane, Methyl pentanoate, Pentyl propanoate, Sulfolane

Supplementary Material Automatic parametrization of non-polar implicit solvent models for the blind prediction of solvation free energies

Bao Wang1, Zhixiong Zhao1, and Guo-Wei Wei1,2,3 ∗ 1Department of Mathematics Michigan State University, MI 48824, USA 2Department of Electrical and Computer Engineering Michigan State University, MI 48824, USA 3Department of Biochemistry and Molecular Biology Michigan State University, MI 48824, USA August 12, 2016

The SAMPL0 molecular information and the predicted solvation free energy with different charge method and atomic radius force ﬁeld parametrization are listed in Table1-4. The SAMPL1-SAMPL4 results are listed in Tables5-20, respectively. For the Sampl0-Sampl2 test sets, the RMS errors that inside and outside the parenthesis denote that when the molecules contain Br atom are included and excluded, respectively. The mean average error (MAE) for different force ﬁeld parametrization are also included. The information of 668 molecules is given in Table 21.

exp pred Table S1: The experimental and predicted solvation free energy for the SAMPL0 test set. ∆G is the experimental solvation free energy, ∆GAM1−BCC, pred pred pred ∆GMulliken, ∆GGasteiger, and ∆GSIESTA are the predicted solvation free energy with four different types of charges. The Amber6 force ﬁeld are employed for the atomic radius parametrization. The energy data are all in the unit of kcal/mol. exp pred pred pred pred Solute Name ∆G ∆GAM1−BCC ∆GMulliken ∆GGasteiger ∆GSIESTA 1,1-diethoxyethane -3.28 -3.30 -1.32 -3.30 -0.28 dimethoxymethane -2.93 -3.66 -1.91 -3.40 -1.96 1-acetoxyethyl acetate -4.97 -6.63 -6.40 -5.79 -5.51 diethyl propanedioate -6.00 -8.27 -6.58 -6.17 -7.14 2-acetoxyethyl acetate -6.34 -7.95 -7.16 -6.72 -6.93 2,3-diacetoxypropyl acetate -8.84 -11.70 -10.34 -9.41 -9.89 1,2-diethoxyethane -3.54 -3.34 -3.77 -3.30 -3.61 1,4-dioxane -5.06 -5.10 -4.58 -4.62 -4.98 benzyl chloride -1.93 -2.90 -2.38 -1.77 -1.79 N,N-4-trimethylbenzamide -9.76 -9.50 -12.32 -13.04 -10.44 ethylsulfanylethane -1.46 -1.56 -1.16 -1.37 -1.59 1-chloro-2-(2-chloroethoxy)ethane -4.23 -6.13 -4.52 -4.76 -4.02 4-methoxy-N,N-dimethyl-benzamide -11.01 -11.28 -10.73 -10.74 -9.95 phenyl formate -3.82 -5.46 -5.34 -5.29 -4.13 m-bis(triﬂuoromethyl)benzene 1.07 1.45 1.04 2.01 1.29 imidazole -9.63 -9.01 -7.18 -6.71 -8.61 benzyl bromide -2.38 -2.78 -1.55 -2.05 NA RMSE 1.30 (1.26) 1.27 (1.25) 1.23 (1.20) 0.99 (NA) ME 0.78 (0.76) -0.18 (-0.12) -0.16 (-0.13) 0.13 (NA)

∗Address correspondences to Guo-Wei Wei. E-mail: [email protected]

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exp pred Table S2: The experimental and predicted solvation free energy for the SAMPL 0 test set. ∆G is the experimental solvation free energy, ∆GAM1−BCC, pred pred pred ∆GMulliken, ∆GGasteiger, and ∆GSIESTA are the predicted solvation free energy with four different types of charges. The Amber bondi force ﬁeld are employed for the atomic radius parametrization. The energy data are all in the unit of kcal/mol. exp pred pred pred pred Solute Name ∆G ∆GAM1−BCC ∆GMulliken ∆GGasteiger ∆GSIESTA 1,1-diethoxyethane -3.28 -3.58 -1.50 -3.75 -1.13 dimethoxymethane -2.93 -3.90 -2.08 -3.77 -2.59 1-acetoxyethyl acetate -4.97 -6.63 -6.46 -5.80 -5.41 diethyl propanedioate -6.00 -8.34 -6.63 -6.21 -7.83 2-acetoxyethyl acetate -6.34 -8.03 -7.28 -6.75 -7.23 2,3-diacetoxypropyl acetate -8.84 -11.99 -10.56 -9.43 -8.67 1,2-diethoxyethane -3.54 -3.29 -3.64 -3.41 -4.09 1,4-dioxane -5.06 -5.24 -4.75 -4.73 -5.44 benzyl chloride -1.93 -3.02 -2.48 -1.80 -2.17 N,N-4-trimethylbenzamide -9.76 -9.43 -12.38 -13.28 -11.40 ethylsulfanylethane -1.46 -1.54 -0.99 -1.41 -1.70 1-chloro-2-(2-chloroethoxy)ethane -4.23 -6.40 -4.71 -4.95 -4.11 4-methoxy-N,N-dimethyl-benzamide -11.01 -11.34 -10.84 -10.90 -10.75 phenyl formate -3.82 -5.55 -5.41 -5.29 -3.69 m-bis(triﬂuoromethyl)benzene 1.07 1.36 0.92 2.07 1.06 imidazole -9.63 -9.01 -7.09 -6.64 -8.49 benzyl bromide -2.38 -2.85 -1.55 -2.09 NA RMSE 1.40 (1.37) 1.30 (1.27) 1.30 (1.27) 0.93 (NA) ME 0.88 (0.86) -0.26 (-0.20) -0.27 (-0.24) -0.12 (NA) 3

exp pred Table S3: The experimental and predicted solvation free energy for the SAMPL 0 test set. ∆G is the experimental solvation free energy, ∆GAM1−BCC, pred pred pred ∆GMulliken, ∆GGasteiger, and ∆GSIESTA are the predicted solvation free energy with four different types of charges. The Amber mbondi2 force ﬁeld are employed for the atomic radius parametrization. The energy data are all in the unit of kcal/mol. exp pred pred pred pred Solute Name ∆G ∆GAM1−BCC ∆GMulliken ∆GGasteiger ∆GSIESTA 1,1-diethoxyethane -3.28 -3.58 -1.50 -3.75 -1.13 dimethoxymethane -2.93 -3.90 -2.08 -3.77 -2.59 1-acetoxyethyl acetate -4.97 -6.63 -6.46 -5.80 -5.41 diethyl propanedioate -6.00 -8.34 -6.63 -6.21 -7.83 2-acetoxyethyl acetate -6.34 -8.03 -7.28 -6.75 -7.23 2,3-diacetoxypropyl acetate -8.84 -11.99 -10.56 -9.43 -8.67 1,2-diethoxyethane -3.54 -3.29 -3.64 -3.41 -4.09 1,4-dioxane -5.06 -5.24 -4.75 -4.73 -5.44 benzyl chloride -1.93 -3.02 -2.48 -1.80 -2.14 N,N-4-trimethylbenzamide -9.76 -9.78 -12.60 -13.41 -12.31 ethylsulfanylethane -1.46 -1.54 -0.99 -1.41 -1.70 1-chloro-2-(2-chloroethoxy)ethane -4.23 -6.40 -4.71 -4.95 -4.12 4-methoxy-N,N-dimethyl-benzamide -11.01 -11.55 -10.97 -10.97 -11.28 phenyl formate -3.82 -5.55 -5.41 -5.29 -3.69 m-bis(triﬂuoromethyl)benzene 1.07 1.36 0.92 2.07 1.06 imidazole -9.63 -8.87 -6.98 -6.59 -7.86 benzyl bromide -2.38 -2.85 -1.55 -2.09 NA RMSE 1.41 (1.37) 1.34 (1.32) 1.33 (1.29) 1.10 (NA) ME 0.91 (0.88) 0.27 (0.21) -0.28 (-0.25) -0.17 (NA)

exp pred Table S4: The experimental and predicted solvation free energy for the SAMPL 0 test set. ∆G is the experimental solvation free energy, ∆GAM1−BCC, pred pred pred ∆GMulliken, ∆GGasteiger, and ∆GSIESTA are the predicted solvation free energy with four different types of charges. The ZAP9 force ﬁeld are employed for the atomic radius parametrization. The energy data are all in the unit of kcal/mol. exp pred pred pred pred Solute Name ∆G ∆GAM1−BCC ∆GMulliken ∆GGasteiger ∆GSIESTA 1,1-diethoxyethane -3.28 -2.27 -0.72 -2.58 -0.82 dimethoxymethane -2.93 -2.44 -1.25 -2.40 -2.21 1-acetoxyethyl acetate -4.97 -6.26 -6.39 -5.66 -5.38 diethyl propanedioate -6.00 -7.87 -6.63 -5.97 -8.06 2-acetoxyethyl acetate -6.34 -7.47 -7.09 -6.43 -7.07 2,3-diacetoxypropyl acetate -8.84 -11.03 -10.34 -9.07 -9.53 1,2-diethoxyethane -3.54 -3.19 -3.52 -3.39 -4.07 1,4-dioxane -5.06 -5.00 -4.77 -4.49 -5.69 benzyl chloride -1.93 -2.67 -2.23 -1.74 -3.15 N,N-4-trimethylbenzamide -9.76 -9.94 -12.14 -13.14 -10.30 ethylsulfanylethane -1.46 -1.41 -1.05 -1.41 -1.85 1-chloro-2-(2-chloroethoxy)ethane -4.23 -6.08 -4.60 -4.58 -4.97 4-methoxy-N,N-dimethyl-benzamide -11.01 -11.00 -10.66 -10.78 -9.95 phenyl formate -3.82 -5.65 -5.51 -5.21 -3.93 m-bis(triﬂuoromethyl)benzene 1.07 3.86 2.42 3.73 2.35 imidazole -9.63 -10.39 -7.24 -6.83 -10.57 benzyl bromide -2.38 -2.85 -1.55 -2.09 NA RMSE 1.33 (1.29) 1.39 (1.37) 1.37 (1.33) 1.08 (NA) ME 0.44 (0.44) 0.00 (0.05) 0.11 (0.12) -0.21 (NA)

exp pred Table S5: The experimental and predicted solvation free energy for the SAMPL 1 test set. ∆G is the experimental solvation free energy, ∆GAM1−BCC, pred pred pred ∆GMulliken, ∆GGasteiger, and ∆GSIESTA are the predicted solvation free energy with four different types of charges. The Amber6 force ﬁeld are employed for the atomic radius parametrization. The energy data are all in the unit of kcal/mol. exp pred pred pred pred Solute Name ∆G ∆GAM1−BCC ∆GMulliken ∆GGasteiger ∆GSIESTA lindane -5.44 -6.72 -4.65 -2.88 -4.40 isobutyl nitrate -1.88 -1.87 -1.80 -1.85 -1.77 butyl nitrate -2.09 -1.95 -1.87 -1.90 -1.42 [(2S)-butan-2-yl] nitrate -1.82 -2.19 -1.97 -1.78 -0.98 1,2-dinitroxyethane -5.73 -3.45 -4.30 -4.01 -4.31 1,2-dinitroxypropane -4.95 -5.58 -4.69 -4.63 -5.02 4

Table 5 – continued from previous page exp pred pred pred pred Solute Name ∆G ∆GAM1−BCC ∆GMulliken ∆GGasteiger ∆GSIESTA ethion -6.10 -6.87 -12.72 -11.38 -12.20 captan -9.01 -7.60 -6.99 -4.56 -7.13 trichloro(nitro)methane -1.45 -0.90 -2.32 -1.93 -3.89 heptachlor -2.55 -4.78 -4.46 -2.44 -5.05 chlordane -3.44 -6.83 -5.88 -2.61 -4.03 dichlobenil -4.71 -3.63 -2.33 -3.72 -5.51 fenuron -9.13 -9.78 -8.32 -8.26 -8.25 N-(3,4-dichlorophenyl)propanimidic acid -7.78 -8.22 -6.24 -7.10 -10.35 alachlor -8.21 -7.57 -7.14 -3.25 -5.86 pebulate -3.64 -4.93 -4.51 -0.93 -5.69 N,N-dipropyl(propylsulfanyl)formamide -4.13 -4.80 -4.22 -0.59 -5.57 dicamba -9.86 -13.10 -7.08 -7.89 -13.94 bensulfuron -17.17 -24.05 -32.80 -30.70 -22.30 3,5,5-trimethylcyclohex-2-en-1-one -5.18 -3.99 -2.61 -2.68 -4.29 1,4,5,8-tetramino-anthraquinone -8.94 -14.62 -10.12 -12.97 -10.82 5-Amino-4-chloro-2-phenylpyridazin-3(2H)-one -16.43 -10.35 -16.16 -16.72 -8.92 1-amino-4-anilino-anthraquinone -7.44 -9.90 -7.81 -11.46 -8.94 4-amino-4’-nitroazobenzene -11.24 -7.95 -9.95 -10.19 -10.73 1-N,1-N-diethyl-2,6-dinitro-4-(trifluoromethyl)benzene-1,3-diamine -5.66 -3.83 -5.10 -10.12 -7.03 terbacil -11.14 -11.48 -6.52 -5.91 -8.68 simazine -10.22 -10.29 -10.24 -5.79 -8.95 aldicarb -9.84 -9.49 -6.79 -6.18 -9.39 carbofuran -9.61 -9.95 -9.22 -7.13 -8.24 trifluralin -3.25 -1.17 -2.69 -9.49 -5.00 nitralin -7.98 -11.34 -17.79 -16.11 -9.29 dinoseb -6.23 -9.67 -7.61 -9.87 -12.93 nitroxyacetone -5.99 -9.84 -8.43 -8.39 -8.14 2-(nitrooxy)ethan-1-ol -8.18 -3.31 -9.26 -7.72 -2.85 N-butyl-N-ethyl-2,6-dinitro-4-(trifluoromethyl)aniline -3.51 -1.34 -2.77 -9.51 -7.93 profluralin -2.45 -0.55 -2.29 -9.60 -5.27 pirimor -9.41 -11.73 -11.70 -8.92 -7.60 4-dimethylamino-azobenzene -6.66 -5.52 -9.75 -10.59 -7.32 endrin -4.82 -7.79 -6.20 -5.24 -4.90 endrin -4.82 -8.03 -7.05 -5.17 -3.73 trichlorfon -12.74 -14.89 -21.45 -3.32 -11.91 chlorfenvinphos -7.07 -5.17 -11.99 -0.59 -2.33 azinphosmethyl -10.03 -14.31 -25.20 -19.17 -15.70 malathion -8.15 -7.89 -11.10 -8.38 -5.75 dialifor -5.74 -11.78 -14.83 -2.20 -3.46 carbophenothion -6.50 -13.81 -17.18 -1.96 -5.61 parathion -6.74 -7.22 -12.74 -9.29 -7.38 methyparathion -7.19 -5.45 -13.67 -8.36 -3.35 chlorpyrifos -5.04 -7.89 -6.71 -11.87 -7.45 diazinon -6.48 -7.90 -9.73 -9.35 -8.44 phorate -4.37 -12.76 -9.48 6.76 -2.95 2-N-ethyl-6-(methylsulfanyl)-4-N-(propan-2-yl)-1,3,5-triazine-2,4-diamine -7.65 -7.46 -15.88 -12.55 -8.62 terbutryn -6.68 -6.26 -14.56 -8.79 -7.97 prometryn -8.43 -5.53 -14.33 -8.63 -7.76 oxamyl -10.18 -17.08 -15.80 -14.00 -15.03 naphthalen-1-yl N-methylcarbamate -9.45 -7.93 -10.97 -8.20 -6.33 thifensulfuron -16.23 -9.92 -20.52 -25.30 -16.30 sulfometuron-methyl -20.25 -15.78 -17.70 -25.08 -21.81 chlorimuronethyl -14.01 -21.38 -13.55 -16.75 -16.46 metsulfuronmethyl -15.54 -15.68 -20.28 -19.84 -24.38 methomyl -10.65 -10.29 -11.80 -9.98 -10.70 endosulfan alpha -4.23 -10.07 -5.22 -19.99 -5.49 bromacil -9.73 -13.28 -15.94 -16.63 NA RMSE 3.26 (3.27) 4.74 (4.77) 4.92 (4.96) 2.92 (NA) 5

Table 5 – continued from previous page exp pred pred pred pred Solute Name ∆G ∆GAM1−BCC ∆GMulliken ∆GGasteiger ∆GSIESTA ME 0.83 (0.88) -2.22 (-2.28) -0.93 (-1.02) -0.52 (NA)

exp pred Table S6: The experimental and predicted solvation free energy for the SAMPL 1 test set. ∆G is the experimental solvation free energy, ∆GAM1−BCC, pred pred pred ∆GMulliken, ∆GGasteiger, and ∆GSIESTA are the predicted solvation free energy with four different types of charges. The Amber Bondi force field are employed for the atomic radius parametrization. The energy data are all in the unit of kcal/mol. exp pred pred pred pred Solute Name ∆G ∆GAM1−BCC ∆GMulliken ∆GGasteiger ∆GSIESTA lindane -5.44 -7.35 -5.20 -3.08 -5.82 isobutyl nitrate -1.88 -1.83 -1.73 -1.85 -1.67 butyl nitrate -2.09 -1.91 -1.83 -1.89 -2.27 [(2S)-butan-2-yl] nitrate -1.82 -2.15 -1.92 -1.77 -1.28 1,2-dinitroxyethane -5.73 -3.47 -4.35 -4.02 -4.23 1,2-dinitroxypropane -4.95 -5.60 -4.70 -4.63 -4.17 ethion -6.10 -6.79 -13.14 -18.19 -10.20 captan -9.01 -7.43 -7.03 -4.39 -7.04 trichloro(nitro)methane -1.45 -0.80 -2.16 -1.81 -3.28 heptachlor -2.55 -5.08 -4.71 -2.53 -5.51 chlordane -3.44 -7.21 -6.19 -2.82 -5.11 dichlobenil -4.71 -3.57 -2.38 -3.68 -5.33 fenuron -9.13 -9.60 -8.26 -8.33 -8.95 N-(3,4-dichlorophenyl)propanimidic acid -7.78 -8.36 -6.31 -7.09 -10.48 alachlor -8.21 -8.38 -8.35 -4.30 -8.71 pebulate -3.64 -4.92 -4.22 -0.45 -5.27 N,N-dipropyl(propylsulfanyl)formamide -4.13 -4.80 -4.10 -0.47 -5.06 dicamba -9.86 -9.90 -5.88 -7.04 -8.14 bensulfuron -17.17 -24.85 -32.86 -40.60 -26.99 3,5,5-trimethylcyclohex-2-en-1-one -5.18 -3.77 -2.44 -2.79 -4.71 1,4,5,8-tetramino-anthraquinone -8.94 -13.96 -9.87 -12.56 -9.90 5-Amino-4-chloro-2-phenylpyridazin-3(2H)-one -16.43 -12.98 -17.00 -17.34 -13.30 1-amino-4-anilino-anthraquinone -7.44 -9.39 -7.71 -11.06 -9.75 4-amino-4’-nitroazobenzene -11.24 -7.82 -10.06 -10.23 -10.50 1-N,1-N-diethyl-2,6-dinitro-4-(trifluoromethyl)benzene-1,3-diamine -5.66 -3.08 -4.70 -10.17 -4.92 terbacil -11.14 -11.10 -6.30 -5.98 -9.27 simazine -10.22 -10.19 -10.01 -5.64 -8.94 aldicarb -9.84 -9.27 -6.83 -6.30 -9.11 carbofuran -9.61 -9.60 -9.08 -7.09 -8.21 trifluralin -3.25 -0.75 -2.48 -9.57 -4.20 nitralin -7.98 -11.29 -18.24 -7.62 -8.76 dinoseb -6.23 -7.63 -6.47 -9.28 -9.35 nitroxyacetone -5.99 -9.96 -8.60 -8.45 -9.19 2-(nitrooxy)ethan-1-ol -8.18 -5.41 -10.48 -9.02 -9.19 N-butyl-N-ethyl-2,6-dinitro-4-(trifluoromethyl)aniline -3.51 -0.96 -2.58 -9.58 -7.93 profluralin -2.45 -0.15 -2.11 -9.65 -4.66 pirimor -9.41 -11.61 -11.48 -9.29 -8.82 4-dimethylamino-azobenzene -6.66 -5.32 -9.77 -10.80 -8.25 endrin -4.82 -8.05 -6.48 -5.46 -5.24 endrin -4.82 -8.21 -7.23 -5.34 -3.99 trichlorfon -12.74 -12.86 -21.20 -2.67 -8.41 chlorfenvinphos -7.07 -8.79 -13.54 -1.20 -9.00 azinphosmethyl -10.03 -14.83 -16.05 -19.48 -14.72 malathion -8.15 -8.22 -11.77 -8.51 -6.92 dialifor -5.74 -15.11 -7.26 -2.98 -9.41 carbophenothion -6.50 -12.90 -8.53 -2.87 -6.04 parathion -6.74 -7.56 -13.06 -9.35 -7.06 methyparathion -7.19 -7.53 -14.54 -8.89 -6.07 chlorpyrifos -5.04 -7.56 -5.73 -11.72 -6.51 6

Table 6 – continued from previous page exp pred pred pred pred Solute Name ∆G ∆GAM1−BCC ∆GMulliken ∆GGasteiger ∆GSIESTA diazinon -6.48 -7.82 -10.45 -9.19 -6.92 phorate -4.37 -13.69 -9.84 7.18 -5.07 2-N-ethyl-6-(methylsulfanyl)-4-N-(propan-2-yl)-1,3,5-triazine-2,4-diamine -7.65 -7.29 -15.13 -12.50 -9.18 terbutryn -6.68 -6.09 -13.76 -9.11 -8.26 prometryn -8.43 -5.34 -13.44 -9.12 -8.27 oxamyl -10.18 -16.60 -15.54 -14.10 -14.79 naphthalen-1-yl N-methylcarbamate -9.45 -8.88 -11.23 -8.33 -8.26 thifensulfuron -16.23 -15.64 -29.47 -21.85 -23.46 sulfometuron-methyl -20.25 -17.84 -19.19 -26.40 -24.56 chlorimuronethyl -14.01 -14.64 -15.46 -19.14 -21.11 metsulfuronmethyl -15.54 -16.98 -21.29 -20.51 -24.56 methomyl -10.65 -10.20 -11.56 -9.88 -11.03 endosulfan alpha -4.23 -9.90 -15.64 -20.47 -5.26 bromacil -9.73 -13.13 -16.11 -17.12 NA RMSE 3.06 (3.07) 4.65 (4.68) 5.52 (5.55) 2.89 (NA) ME 0.96 (0.99) -2.22 (-2.28) -1.16 (-1.26) -1.15 (NA)

exp pred Table S7: The experimental and predicted solvation free energy for the SAMPL 1 test set. ∆G is the experimental solvation free energy, ∆GAM1−BCC, pred pred pred ∆GMulliken, ∆GGasteiger, and ∆GSIESTA are the predicted solvation free energy with four different types of charges. The Amber mbondi2 force field are employed for the atomic radius parametrization. The energy data are all in the unit of kcal/mol. exp pred pred pred pred Solute Name ∆G ∆GAM1−BCC ∆GMulliken ∆GGasteiger ∆GSIESTA lindane -5.44 -7.35 -5.20 -3.08 -5.55 isobutyl nitrate -1.88 -1.83 -1.73 -1.85 -1.67 butyl nitrate -2.09 -1.91 -1.83 -1.89 -2.27 [(2S)-butan-2-yl] nitrate -1.82 -2.15 -1.92 -1.77 -1.28 1,2-dinitroxyethane -5.73 -3.47 -4.35 -4.02 -4.23 1,2-dinitroxypropane -4.95 -5.60 -4.70 -4.63 -4.17 ethion -6.10 -6.79 -13.14 -18.19 -10.20 captan -9.01 -7.77 -7.37 -4.67 -7.60 trichloro(nitro)methane -1.45 -0.80 -2.16 -1.81 -3.28 heptachlor -2.55 -5.08 -4.71 -2.53 -5.12 chlordane -3.44 -7.21 -6.19 -2.82 -4.57 dichlobenil -4.71 -3.57 -2.38 -3.68 -5.30 fenuron -9.13 -9.57 -8.28 -8.38 -9.40 N-(3,4-dichlorophenyl)propanimidic acid -7.78 -8.21 -6.19 -6.98 -9.92 alachlor -8.21 -8.38 -8.35 -4.30 -8.71 pebulate -3.64 -5.06 -4.31 -0.55 -5.71 N,N-dipropyl(propylsulfanyl)formamide -4.13 -4.93 -4.19 -0.56 -5.49 dicamba -9.86 -9.90 -5.88 -7.04 -8.04 bensulfuron -17.17 -21.47 -32.66 -21.88 -24.75 3,5,5-trimethylcyclohex-2-en-1-one -5.18 -3.77 -2.44 -2.79 -4.71 1,4,5,8-tetramino-anthraquinone -8.94 -13.10 -8.88 -11.48 -7.76 5-Amino-4-chloro-2-phenylpyridazin-3(2H)-one -16.43 -12.93 -16.88 -17.20 -12.96 1-amino-4-anilino-anthraquinone -7.44 -8.91 -7.42 -10.83 -8.71 4-amino-4’-nitroazobenzene -11.24 -7.44 -9.82 -9.96 -9.92 1-N,1-N-diethyl-2,6-dinitro-4-(trifluoromethyl)benzene-1,3-diamine -5.66 -2.58 -4.27 -9.79 -4.10 terbacil -11.14 -10.80 -6.08 -5.85 -8.59 simazine -10.22 -9.43 -9.43 -5.21 -7.87 aldicarb -9.84 -9.09 -6.71 -6.20 -9.24 carbofuran -9.61 -9.46 -9.01 -7.05 -7.81 trifluralin -3.25 -0.78 -2.46 -9.49 -4.20 nitralin -7.98 -11.32 -18.23 -7.56 -8.75 dinoseb -6.23 -7.63 -6.47 -9.28 -9.35 nitroxyacetone -5.99 -9.96 -8.60 -8.45 -9.19 7

Table 7 – continued from previous page exp pred pred pred pred Solute Name ∆G ∆GAM1−BCC ∆GMulliken ∆GGasteiger ∆GSIESTA 2-(nitrooxy)ethan-1-ol -8.18 -5.41 -10.48 -9.02 -9.19 N-butyl-N-ethyl-2,6-dinitro-4-(triﬂuoromethyl)aniline -3.51 -0.99 -2.55 -9.49 -7.93 proﬂuralin -2.45 -0.18 -2.08 -9.56 -4.64 pirimor -9.41 -11.68 -11.55 -9.31 -9.21 4-dimethylamino-azobenzene -6.66 -5.49 -10.00 -10.95 -9.34 endrin -4.82 -8.05 -6.48 -5.46 -4.71 endrin -4.82 -8.21 -7.23 -5.34 -3.53 trichlorfon -12.74 -12.86 -21.20 -2.67 -8.41 chlorfenvinphos -7.07 -8.79 -13.54 -1.20 -9.00 azinphosmethyl -10.03 -14.92 -16.09 -19.47 -14.82 malathion -8.15 -8.22 -1.77 -8.51 -6.92 dialifor -5.74 -15.11 -7.26 -2.98 -9.41 carbophenothion -6.50 -12.90 -8.53 -2.87 -6.04 parathion -6.74 -7.56 -3.06 -9.35 -7.06 methyparathion -7.19 -7.53 -4.54 -8.89 -6.07 chlorpyrifos -5.04 -7.56 -15.73 -11.72 -6.51 diazinon -6.48 -7.82 -10.45 -9.19 -6.92 phorate -4.37 -13.69 -9.84 7.18 -5.07 2-N-ethyl-6-(methylsulfanyl)-4-N-(propan-2-yl)-1,3,5-triazine-2,4-diamine -7.65 -7.78 -15.38 -13.12 -10.85 terbutryn -6.68 -6.05 -13.80 -9.39 -8.86 prometryn -8.43 -5.36 -13.50 -9.45 -8.93 oxamyl -10.18 -16.49 -15.43 -14.05 -14.71 naphthalen-1-yl N-methylcarbamate -9.45 -9.00 -11.29 -8.40 -8.48 thifensulfuron -16.23 -25.73 -28.92 -24.53 -23.85 sulfometuron-methyl -20.25 -27.46 -28.96 -17.81 -24.05 chlorimuronethyl -14.01 -14.22 -25.18 -8.44 -20.75 metsulfuronmethyl -15.54 -16.84 -31.13 -19.87 -24.39 methomyl -10.65 -10.17 -11.48 -9.79 -11.03 endosulfan alpha -4.23 -9.90 -15.64 -20.47 -5.26 bromacil -9.73 -13.55 -16.54 -17.47 NA RMSE 3.29 (3.30) 5.39 (5.41) 4.76 (4.82) 2.82 (NA) ME 1.17 (1.22) -2.32 (-2.39) -0.56 (-0.67) -1.05 (NA)

exp pred Table S8: The experimental and predicted solvation free energy for the SAMPL 1 test set. ∆G is the experimental solvation free energy, ∆GAM1−BCC, pred pred pred ∆GMulliken, ∆GGasteiger, and ∆GSIESTA are the predicted solvation free energy with four different types of charges. The ZAP9 ﬁeld are employed for the atomic radius parametrization. The energy data are all in the unit of kcal/mol. exp pred pred pred pred Solute Name ∆G ∆GAM1−BCC ∆GMulliken ∆GGasteiger ∆GSIESTA lindane -5.44 -7.29 -5.26 -3.27 -5.99 isobutyl nitrate -1.88 -1.84 -1.74 -1.83 -2.44 butyl nitrate -2.09 -1.90 -1.83 -1.88 -2.63 [(2S)-butan-2-yl] nitrate -1.82 -2.15 -1.95 -1.72 -1.43 1,2-dinitroxyethane -5.73 -3.47 -4.26 -4.06 -3.73 1,2-dinitroxypropane -4.95 -5.50 -4.61 -4.64 -4.50 ethion -6.10 -12.14 -12.52 -18.74 -9.43 captan -9.01 -8.27 -6.85 -5.65 -6.04 trichloro(nitro)methane -1.45 -0.90 -1.74 -1.41 -0.76 heptachlor -2.55 -5.18 -4.61 -2.73 -4.40 chlordane -3.44 -6.98 -5.92 -3.14 -6.89 dichlobenil -4.71 -3.85 -2.53 -3.61 -2.33 fenuron -9.13 -7.28 -7.30 -7.68 -8.23 N-(3,4-dichlorophenyl)propanimidic acid -7.78 -8.32 -6.46 -6.69 -9.77 alachlor -8.21 -8.75 -7.86 -5.64 -9.14 pebulate -3.64 -5.30 -4.06 1.45 -5.66 N,N-dipropyl(propylsulfanyl)formamide -4.13 -5.21 -3.90 1.56 -5.81 8

Table 8 – continued from previous page exp pred pred pred pred Solute Name ∆G ∆GAM1−BCC ∆GMulliken ∆GGasteiger ∆GSIESTA dicamba -9.86 -9.96 -6.54 -6.68 -6.74 bensulfuron -17.17 -26.51 -32.14 -41.69 -20.94 3,5,5-trimethylcyclohex-2-en-1-one -5.18 -3.47 -2.53 -2.22 -4.47 1,4,5,8-tetramino-anthraquinone -8.94 -17.00 -10.66 -10.73 -8.06 5-Amino-4-chloro-2-phenylpyridazin-3(2H)-one -16.43 -12.95 -14.96 -14.70 -12.38 1-amino-4-anilino-anthraquinone -7.44 -9.73 -8.06 -10.03 -5.16 4-amino-4’-nitroazobenzene -11.24 -9.35 -10.29 -9.56 -9.64 1-N,1-N-diethyl-2,6-dinitro-4-(trifluoromethyl)benzene-1,3-diamine -5.66 0.44 -1.54 -7.64 5.31 terbacil -11.14 -7.63 -5.85 -5.12 -5.16 simazine -10.22 -12.35 -9.62 -4.52 -7.43 aldicarb -9.84 -6.80 -6.33 -5.47 -7.32 carbofuran -9.61 -8.01 -8.52 -6.86 -7.34 trifluralin -3.25 2.33 0.16 -7.52 6.82 nitralin -7.98 -8.06 -10.88 -16.91 -3.83 dinoseb -6.23 -8.41 -6.55 -8.59 -6.54 nitroxyacetone -5.99 -10.33 -9.32 -8.86 -7.61 2-(nitrooxy)ethan-1-ol -8.18 -6.53 -10.14 -9.10 -8.13 N-butyl-N-ethyl-2,6-dinitro-4-(trifluoromethyl)aniline -3.51 2.16 0.09 -7.54 5.02 profluralin -2.45 2.86 0.47 -7.69 6.76 pirimor -9.41 -9.57 -9.86 -7.84 -6.34 4-dimethylamino-azobenzene -6.66 -4.93 -9.24 -10.49 -6.71 endrin -4.82 -7.35 -5.91 -5.20 -5.60 endrin -4.82 -7.87 -6.80 -5.25 -5.26 trichlorfon -12.74 -11.29 -16.22 -3.50 -9.32 chlorfenvinphos -7.07 -8.36 -18.50 -3.41 -8.58 azinphosmethyl -10.03 -15.99 -18.71 -19.79 -13.95 malathion -8.15 -8.59 -15.42 -8.18 -6.23 dialifor -5.74 -14.48 -20.25 -4.48 -9.40 carbophenothion -6.50 -12.13 -18.47 -2.09 -3.59 parathion -6.74 -8.20 -17.80 -9.26 -8.07 methyparathion -7.19 -7.63 -18.93 -9.05 -6.44 chlorpyrifos -5.04 -5.38 -9.98 -10.56 -5.70 diazinon -6.48 -7.90 -15.19 -9.49 -7.66 phorate -4.37 -12.68 -15.88 3.85 -5.39 2-N-ethyl-6-(methylsulfanyl)-4-N-(propan-2-yl)-1,3,5-triazine-2,4-diamine -7.65 -5.07 -14.11 -12.56 -7.95 terbutryn -6.68 -4.17 -13.16 -9.35 -7.41 prometryn -8.43 -3.20 -13.05 -9.40 -8.46 oxamyl -10.18 -17.63 -15.41 -13.74 -14.82 naphthalen-1-yl N-methylcarbamate -9.45 -8.93 -10.88 -8.63 -9.52 thifensulfuron -16.23 -29.08 -28.50 -23.14 -21.81 sulfometuron-methyl -20.25 -28.98 -30.86 -17.47 -25.88 chlorimuronethyl -14.01 -24.75 -25.29 -6.96 -20.37 metsulfuronmethyl -15.54 -20.18 -23.92 -20.91 -26.29 methomyl -10.65 -11.47 -11.39 -10.28 -9.47 endosulfan alpha -4.23 -9.83 -17.67 -14.11 -5.88 bromacil -9.73 -13.52 -15.80 -20.25 NA RMSE 4.26 (4.35) 6.16 (6.16) 5.33 (5.45) 3.76 (NA) ME 1.26 (1.30) -3.01 (-3.06) -0.66 (-0.82) 0.31 (NA)

Table 21 lists the information of 668 molecules used in this work, where the PubChem ID, molecular name, and experimental solvation free energy is provided. Furthermore, we provide the source of molecules and their experimental data. 9

exp pred Table S9: The experimental and predicted solvation free energy for the SAMPL 2 test set. ∆G is the experimental solvation free energy, ∆GAM1−BCC, pred pred pred ∆GMulliken, ∆GGasteiger, and ∆GSIESTA are the predicted solvation free energy with four different types of charges. The Amber6 force field are employed for the atomic radius parametrization. The energy data are all in the unit of kcal/mol. exp pred pred pred pred Solute Name ∆G ∆GAM1−BCC ∆GMulliken ∆GGasteiger ∆GSIESTA (+-)ibuprofen -7.00 -4.86 -9.88 -8.47 -5.73 glycerol -13.43 -13.97 -13.28 -14.57 -14.67 hexachloroethane -0.64 -1.36 -1.92 -0.43 -1.29 hexachlorobenzene -2.33 -0.64 -1.62 -3.28 -3.70 Trimethyl phosphate -8.70 -8.88 -3.20 -3.82 -6.35 phthalimide -9.61 -10.84 -9.60 -10.33 -10.68 pentachloronitrobenzene -5.22 -1.00 -2.61 -6.66 -8.86 caffeine -12.64 -14.07 -13.31 -10.36 -12.01 Ketoprofen -10.78 -11.90 -13.91 -11.49 -8.92 Flurbiprofen -8.42 -3.88 -5.12 -2.67 -3.87 naproxen -10.21 -11.71 -12.36 -9.84 -9.17 diflunisal -9.40 -13.30 -12.20 -12.47 -15.30 acetylsalicylic acid -9.94 -10.39 -10.58 -9.34 -9.37 octafluorocyclobutane 3.43 5.29 4.42 5.20 3.73 Uracil -16.59 -16.77 -12.89 -11.10 -15.13 5-fluorouracil -16.92 -16.22 -11.52 -10.51 -13.21 5-chlorouracil -17.74 -14.53 -9.63 -4.37 -10.32 6-chlorouracil -15.83 -12.96 -8.81 -5.24 -10.32 5-trifluoromethyluracil -15.46 -17.22 -8.39 -4.85 -9.89 cyanuric acid -18.06 -16.90 -13.34 -10.06 -9.20 D-xylose -20.52 -16.88 -19.95 -18.57 -17.44 D-glucose -25.47 -22.61 -23.96 -25.26 -22.44 1,1,1-trifluoro-2,2,2-trimethoxyethane -0.80 1.27 -2.14 -1.92 2.09 propyl paraben -9.37 -9.14 -6.56 -7.30 -10.79 butyl paraben -8.72 -9.31 -6.75 -7.28 -9.70 methyl paraben -9.51 -10.22 -7.11 -7.93 -11.70 ethyl paraben -9.20 -9.73 -6.87 -7.50 -11.30 sulfolane -8.61 -8.58 -10.99 -7.01 -9.04 5-bromouracil -18.17 -15.70 -12.74 -11.49 NA RMSE 2.09 (2.11) 3.51 (3.59) 4.78 (4.86) 3.46 (NA) ME -0.59 (-0.65) 1.56 (1.65) 2.51 (2.65) 1.18 (NA)

Table S21: List of 668 molecules involved in the work. In the column of “Remark”, we provide the source of the experimental solvation free energies, in which we employ the following abbreviations. M: molecule is contained in the Mobley’s database. S1: molecule from the SAMPL1 set. S2: molecule from the SAMPL2 set. G: molecule from the paper entitled “Group Contributions to the Thermodynamic Properties of Non-Ionic Organic Solutes in Dilute Aqueous Solution. Sergio Cabani et al. Journal of Solution Chemistry, 1981, Vol 10, No. 8”. K: molecule from the paper entitled “Solvation Model Based on Weighted Solvent Accessible Surface Area, Junmei Wang, et al., J. Phys. Chem. B, 2001, 105, 5055-5067”. T: molecule from the paper entitled “Extension of the platform of applicability of the SM5.42R universal solvation model, Jiabo Li et al., Theoretical Chemistry Accounts. 1999, 103, 9-63”. PubChem ID Solute Name ∆GExp Remark 8079 cyclohexene 0.14 M 10740 1,1-diphenylethene -2.78 M 8418 anthracene -3.95 S2 11903 1-ethyl-2-methylbenzene -0.85 M 11940 9,10-dihydroanthracene -3.78 M 6324 ethane 1.83 M 7095 biphenyl -2.70 M 18927701 1,1,1-trifluoro-2,2,2-trimethoxyethane -0.80 M 8263 octafluorocyclobutane 3.43 M 223106 m-bis(trifluoromethyl)benzene 1.07 M 21269179 1,2,2-trifluoroethoxybenzene -1.29 M 11638 fluoromethane -0.22 M 6368 1,1-difluoroethane -0.11 M 6373 Trifluoromethane 0.81 G 7368 trifluoromethylbenzene -0.25 M 8302 1,1,2,3,3,3-Hexafluoro-1-propene 2.31 G 9818 1,2-bis(trifluoromethyl)benzene 1.07 M 10

Table 21 – continued from previous page PubChem ID Solute Name ∆GExp Remark 6326 Ethyne -0.01 G 6335 prop-1-yne -0.48 M 7846 but-1-yne -0.16 M 12309 pent-1-yne 0.01 M 12350 hept-1-yne 0.60 M 12370 oct-1-yne 0.71 M 12732 hex-1-yne 0.29 M 18937 1-Nonyne 1.05 K 6325 ethylene 1.28 M 7844 but-1-ene 1.38 M 8004 pent-1-ene 1.68 M 8125 1-OCTENE 2.08 M 8252 prop-1-ene 1.32 M 8255 2-methylprop-1-ene 1.16 M 10553 2-methylbut-2-ene 1.31 M 11239 3-methylbut-1-ene 1.83 M 11574 1-methylcyclohexene 0.67 M 11597 hex-1-ene 1.58 M 11610 hept-1-ene 1.66 M 11611 hept-2-ene 1.68 M 12724 4-Methyl-1-pentene 1.91 G 12986 2-methylpent-1-ene 1.47 M 31285 non-1-ene 2.06 M 639662 trans-2-Heptene 1.66 K 5326160 cis-2-PENTENE 1.31 K 5326161 trans-2-Pentene 1.34 K 8882 cyclopentene 0.56 M 6557 isoprene 0.68 M 7845 butadiene 0.56 M 10566 2,3-dimethylbuta-1,3-diene 0.40 M 11587 penta-1,4-diene 0.93 M 11598 hexa-1,5-diene 1.01 M 11000 cyclohepta-1,3,5-triene -0.99 M 7407 isopropenylbenzene -1.24 M 7501 styrene -1.24 S1 11904 2-methylstyrene -1.24 G 356 octane 2.88 M 6334 propane 2.00 M 6351 cyclopropane 0.75 M 6360 isobutane 2.30 M 6403 2,2-dimethylbutane 2.51 M 6556 isopentane 2.38 M 6589 2,3-dimethylbutane 2.34 M 7282 3-methylpentane 2.51 M 7296 methylcyclopentane 1.59 M 7843 n-butane 2.10 M 7892 isohexane 2.51 M 7907 2,4-dimethylpentane 2.83 M 7962 methylcyclohexane 1.70 M 8003 n-pentane 2.30 M 8058 hexane 2.48 M 8078 cyclohexane 1.23 M 8141 nonane 3.13 M 8900 heptane 2.67 M 9253 cyclopentane 1.20 M 9265 Cycloheptane 0.80 G 9266 Cyclooctane 0.86 G 10041 neopentane 2.51 M 11

Table 21 – continued from previous page PubChem ID Solute Name ∆GExp Remark 10907 2,2,4-trimethylpentane 2.89 M 11229 3,3-dimethylpentane 2.56 M 11260 2,3-dimethylpentane 2.52 M 11269 2,3,4-trimethylpentane 2.56 M 11416 1,2-dimethylcyclohexane 1.58 M 11507 3-methylhexane 2.71 M 11519 3-methylheptane 2.97 M 11523 1,4-dimethylcyclohexane 2.11 M 11542 2,2-dimethylpentane 2.88 M 11582 2-methylhexane 2.93 M 15600 decane 3.16 M 16270 propylcyclopentane 2.13 M 16628 cis-1,2-Dimethylcyclohexane 1.58 G 19041 2,2,5-trimethylhexane 2.93 M 19540 pentylcyclopentane 2.55 M 931 naphthalene -2.40 M 10008 ﬂuorobenzene -0.80 M 995 phenanthrene -3.88 M 1140 toluene -0.90 M 6734 acenaphthene -3.15 M 6853 9H-ﬂuorene -3.35 M 7002 1-methylnaphthalene -2.44 M 7237 o-xylene -0.90 M 7247 1,2,4-trimethylbenzene -0.86 M 7366 tert-butylbenzene -0.44 M 7406 cumene -0.30 M 7463 1-isopropyl-4-methyl-benzene -0.68 M 7500 ethylbenzene -0.79 M 7580 1,1’-Methylenebisbenzene -2.82 G 7668 propylbenzene -0.53 M 7705 butylbenzene -0.40 M 7809 p-xylene -0.80 M 7929 m-xylene -0.83 M 7947 mesitylene -0.90 M 8680 sec-butylbenzene -0.45 M 10326 indane -1.46 M 10686 1,2,3-trimethylbenzene -1.21 M 10864 pentylbenzene -0.23 M 10870 isobutylbenzene 0.16 M 11304 1,4-dimethylnaphthalene -2.82 M 11327 1,3-dimethylnaphthalene -2.47 M 11386 2,3-dimethylnaphthalene -2.78 M 11387 2,6-dimethylnaphthalene -2.63 M 12160 1-ethyl-4-methyl-benzene -0.95 M 14109 hexylbenzene -0.04 M 14315 1-ethylnaphthalene -2.40 M 16295 1,1-Dimethylpropyl benzene -0.18 G 31423 pyrene -4.52 M 12720 1-Buten-3-yne 0.04 K 297 methane 2.00 M 9216 dibenzo-p-dioxin -3.15 M 31275 1,4-dioxane -5.06 M 10722 2-methylbenzaldehyde -3.93 M 8908 hexyl acetate -2.26 M 26447 (2S,5R)-2-isopropyl-5-methylcyclohexanone -2.53 M 16666 (1R,2S,5R)-2-isopropyl-5-methylcyclohexanol -3.20 M 6251 (2R,3R,4R,5R)-Hexan-1,2,3,4,5,6-hexol -23.62 M 6997 2-ethylphenol -5.66 M 12

Table 21 – continued from previous page PubChem ID Solute Name ∆GExp Remark 8894 tetrahydropyran -3.12 M 7583 diphenyl ether -2.87 M 7043 1,2-dimethoxybenzene -5.33 M 16441 4-(1-Methylethenyl)-1-cyclohexene-1-carboxaldehyde -4.09 M 6998 2-hydroxybenzaldehyde -4.68 M 442474 (3R)-3,7-Dimethylocta-1,6-dien-3-yl acetate -2.49 M 8095 2-ethoxyethyl acetate -5.31 M 22227 (2R,5R)-2-methyl-5-(1-methylethenyl)-cyclohexanone -3.75 M 61362 6-isopropyl-3-methyl-1-cyclohex-2-enone -4.51 M 94221 (1S,5R)-2-methyl-5-(1-methylethenyl)-2-cyclohexen-1-ol -4.44 M 637566 (2E)-3,7-dimethylocta-2,6-dien-1-ol -4.45 M 643820 (2Z)-3,7-dimethylocta-2,6-dien-1-ol -4.78 M 21210 1-butoxy-2-propanol -5.73 M 460 2-methoxyphenol -5.94 M 7144 4-methyl-2-methoxyphenol -5.80 M 17739 4-propylguaiacol -5.26 M 7041 2,6-dimethoxyphenol -6.96 M 3394 Flurbiprofen -8.42 M 3672 (+-)ibuprofen -7.00 M 753 glycerol -13.43 M 3825 Ketoprofen -10.78 M 3059 diﬂunisal -9.40 M 156391 naproxen -10.21 M 2244 acetylsalicylic acid -9.94 M 135191 D-xylose -20.52 S2 5793 D-glucose -25.47 S2 7175 propyl paraben -9.37 M 7184 butyl paraben -8.72 M 7456 methyl paraben -9.51 M 8434 ethyl paraben -9.20 M 6544 3,5,5-trimethylcyclohex-2-en-1-one -5.18 M 7765 1,1-diethoxyethane -3.28 M 8020 dimethoxymethane -2.93 M 222536 1-acetoxyethyl acetate -4.97 M 7761 diethyl propanedioate -6.00 M 8121 2-acetoxyethyl acetate -6.34 M 5541 2,3-diacetoxypropyl acetate -8.84 M 12375 1,2-diethoxyethane -3.54 M 74626 phenyl formate -3.82 M 69720 trimethoxymethylbenzene -4.04 M 84440 diethoxymethoxybenzene -5.23 M 9005 trimethoxymethane -4.42 M 15050 1,1,1-trimethoxyethane -4.42 M 141897 1,1,1,2-tetramethoxyethane -5.73 M 177 acetaldehyde -3.50 M 261 butanal -3.18 M 454 octanal -2.29 M 527 propanal -3.43 M 712 formaldehyde -2.75 M 6184 hexanal -2.81 M 6561 2-methylpropanal -2.86 M 8063 pentanal -3.03 M 8130 heptanal -2.67 M 31289 nonanal -2.07 M 240 benzaldehyde -4.02 M 176 acetic acid -6.69 M 264 butyric acid -6.35 M 1032 propionic acid -6.46 M 13

Table 21 – continued from previous page PubChem ID Solute Name ∆GExp Remark 7991 pentanoic acid -6.16 M 8892 hexanoic acid -6.21 M 10430 3-methylbutanoic acid -6.09 M 6584 methyl acetate -3.13 M 7351 isobutyl 2-methylpropanoate -1.69 M 7749 ethyl propanoate -2.68 M 7762 ethyl butanoate -2.49 M 7770 propyl butanoate -2.28 M 7797 Heptanoic acid ethyl ester -2.30 G 7803 propyl propanoate -2.44 M 7824 methyl hexanoate -2.49 M 7915 isopropyl acetate -2.64 M 7997 propyl acetate -2.79 M 8038 isobutyl acetate -2.36 M 8091 methyl octanoate -2.04 M 8857 ethyl acetate -2.94 M 10882 ethyl pentanoate -2.49 M 11124 methyl propanoate -2.93 M 12180 methyl butanoate -2.83 M 12206 methyl pentanoate -2.56 M 12217 pentyl propanoate -2.11 M 12348 pentyl acetate -2.51 M 12508 Propanoic acid 1-methylethyl ester -2.22 G 20748 methyl cyclohexanecarboxylate -3.30 M 31265 ethyl hexanoate -2.23 M 31272 butyl acetate -2.64 M 31276 isopentyl acetate -2.21 M 69027 methyl 2,2-dimethylpropanoate -2.40 M 76122 methyl cyclopropanecarboxylate -4.10 M 31249 diethyl butanedioate -5.71 M 7150 methyl benzoate -3.92 M 7165 ethyl benzoate -3.64 M 66750 1,2-ethanediol -7.75 G 180 acetone -3.80 M 6416 3,3-dimethylbutan-2-one -3.11 M 6569 butanone -3.71 G 7288 3-PENTANONE -3.41 M 7895 pentan-2-one -3.52 M 7909 4-methylpentan-2-one -3.05 M 7967 cyclohexanone -4.91 M 8051 heptan-2-one -3.04 M 8093 octan-2-one -2.88 M 8163 2-Undecanone -2.16 M 8452 cyclopentanone -4.70 M 10405 5-Nonanone -2.65 M 11251 3-methylbutan-2-one -3.24 M 11271 2,4-dimethylpentan-3-one -2.74 M 11583 hexan-2-one -3.28 M 12741 decan-2-one -2.34 M 13004 1-cyclopropylethanone -4.61 M 13187 nonan-2-one -2.49 M 13207 1-cyclohexylethanone -3.90 M 31246 heptan-4-one -2.92 M 64151 2-Adamantanone -4.46 T 7410 1-phenylethanone -4.58 M 8500 1-(p-tolyl)ethanone -4.70 M 263 butan-1-ol -4.72 M 702 ethanol -5.00 M 14

Table 21 – continued from previous page PubChem ID Solute Name ∆GExp Remark 887 methanol -5.10 M 957 octan-1-ol -4.09 M 1031 propan-1-ol -4.85 M 3776 propan-2-ol -4.74 M 6276 pentan-1-ol -4.57 M 6386 2-methylpropan-2-ol -4.47 M 6405 2-methylbutan-2-ol -4.43 M 6560 2-methylpropan-1-ol -4.50 M 6568 butan-2-ol -4.62 M 7298 cyclopentanol -5.49 M 7910 4-methylpentan-2-ol -3.73 M 7966 cyclohexanol -5.46 M 8103 hexan-1-ol -4.40 M 8129 heptan-1-ol -4.21 M 8174 Decyl Alcohol -3.64 M 8723 2-methylbutan-1-ol -4.42 M 8914 1-Nonanol -3.89 M 10399 cycloheptanol -5.48 M 11264 2-methylpentan-3-ol -3.88 M 11428 pentan-3-ol -4.35 M 11513 4-Heptanol -4.01 K 11543 2-methylpentan-2-ol -3.92 M 11670 2,3-Dimethyl-2-butanol -3.91 K 12178 hexan-3-ol -4.06 M 22386 pentan-2-ol -4.39 M 31260 3-methylbutan-1-ol -4.42 M 962 H2O -6.30 T 174 ethylene glycol -9.30 M 244 phenylmethanol -6.62 M 6054 2-phenylethanol -6.79 M 31234 3-phenylpropan-1-ol -6.92 M 335 o-cresol -5.90 M 342 m-cresol -5.49 M 9707 2-ﬂuorophenol -5.29 M 996 Phenol -6.61 M 2879 p-cresol -6.13 M 7005 naphthalen-1-ol -7.67 M 7249 3,4-dimethylphenol -6.50 M 7267 2,5-dimethylphenol -5.91 M 7393 4-tert-butylphenol -5.91 M 7771 2,4-dimethylphenol -6.01 M 7948 3,5-dimethylphenol -6.27 M 8663 naphthalen-2-ol -8.11 M 10687 2,3-dimethylphenol -6.16 M 11335 2,6-dimethylphenol -5.26 M 12101 3-ethylphenol -6.25 M 12580 4-propylphenol -5.21 M 31242 4-ethylphenol -6.13 M 3283 ethoxyethane -1.59 M 7301 2-methyltetrahydrofuran -3.30 M 7914 2-isopropoxypropane -0.53 M 8028 tetrahydrofuran -3.47 M 8114 1-propoxypropane -1.16 M 8254 methoxymethane -1.91 M 8909 1-butoxybutane -0.83 M 10903 methoxyethane -2.10 M 11182 1-methoxypropane -1.66 M 11721 2-methoxypropane -2.01 M 15

Table 21 – continued from previous page PubChem ID Solute Name ∆GExp Remark 12340 1-Ethoxypropane -1.81 G 12586 1,3-Dioxolane -4.10 K 13855 2,5-dimethyltetrahydrofuran -2.92 M 15413 2-methoxy-2-methyl-propane -2.21 M 8071 1,2-dimethoxyethane -4.84 M 7519 anisole -2.45 M 7674 ethoxybenzene -2.22 M 16900 oct-2-enal -3.43 M 447466 but-2-enal -4.22 M 5281168 (2E)-hex-2-enal -3.68 M 5283324 E-oct-2-enal -3.44 K 637564 trans,trans-2,4-Hexadienal -4.63 K 101 3-hydroxybenzaldehyde -9.52 M 126 4-hydroxybenzaldehyde -8.83 M 7865 methyl formate -2.78 M 8025 ethyl formate -2.56 M 8052 isopentyl formate -2.13 M 12257 isopropyl formate -2.02 M 7476 1-(4-methoxyphenyl)ethanone -4.40 M 9893 methyl 2,2,2-trifluoroacetate -1.10 M 6027 (2S,3R,4S,5R)-oxane-2,3,4,5-tetrol -20.52 M 64689 (2R,3R,4S,5S,6R)-6-(hydroxymethyl)tetrahydropyran-2,3,4,5-tetrol -25.47 M 7858 prop-2-en-1-ol -5.03 M 8019 2-methoxyethanol -6.62 M 8076 2-ethoxyethanol -6.69 M 8133 2-butoxyethanol -6.25 M 17756 2-propoxyethanol -6.40 M 6409 2,2,2-trifluoroethanol -4.31 M 9774 1,1,1-trifluoropropan-2-ol -4.16 M 6993809 111-trifluoropropan-2-ol -4.20 M 6441 2,2,3,3-Tetrafluoropropan-1-ol -4.88 G 13529 1,1,1,3,3,3-Hexafluoro-propan-2-ol -3.77 G 9872 2,2,3,3,3-Pentafluoro-propan-1-ol -4.15 G 9007 3-methoxyphenol -7.66 M 8082 piperidine -5.11 M 2160 Amitriptyline -7.43 M 77918 1-benzylimidazole -7.63 M 4044 2-(2,3-dimethylphenyl)aminobenzoic acid -6.78 M 30209 HEXYL NITRATE -1.66 M 96257 3-nitrooxypropyl nitrate -4.80 M 138747 1,3-bis-(nitrooxy)butane -4.29 M 31420 1,4-diamino-9,10-anthracenedione -11.85 M 6710 1-amino-9,10-anthracenedione -9.44 M 8341 2-amino-9,10-anthraquinone -11.53 M 20528 1-(2-hydroxyethylamino)-9,10-anthraquinone -14.21 M 8323 1-amino-4-hydroxy-9,10-anthracenedione -9.53 M 3100 [2-benzhydryloxyethyl]-dimethyl-amine -9.34 M 15758 5-chlorouracil -17.74 M 73272 6-chlorouracil -15.83 M 3385 5-fluorouracil -16.92 M 5899 5-trifluoromethyluracil -15.46 M 5802 5-bromouracil -18.17 M 1174 Uracil -16.59 S2 7956 cyanuric acid -18.06 M 6809 phthalimide -9.61 M 2519 caffeine -12.64 M 10541 Trimethyl phosphate -8.70 M 14215 pebulate -3.64 M 16

Table 21 – continued from previous page PubChem ID Solute Name ∆GExp Remark 16003 N,N-dipropyl(propylsulfanyl)formamide -4.13 M 6053 4-dimethylamino-azobenzene -6.66 S1 3031 dichlobenil -4.71 M 34468 1-N,1-N-diethyl-2,6-dinitro-4-(trifluoromethyl)benzene-1,3-diamine -5.66 M 5569 trifluralin -3.25 M 2319 N-butyl-N-ethyl-2,6-dinitro-4-(trifluoromethyl)aniline -3.51 M 33500 profluralin -2.45 M 56160 chlorimuronethyl -14.01 S1 15546 5-Amino-4-chloro-2-phenylpyridazin-3(2H)-one -16.43 M 107828 bensulfuron -17.17 S1 91729 thifensulfuron -16.23 S1 52997 sulfometuron-methyl -20.25 S1 52999 metsulfuronmethyl -15.54 S1 9411 bromacil -9.73 M 10974 isobutyl nitrate -1.88 M 13567 butyl nitrate -2.09 M 79123 [(2S)-butan-2-yl] nitrate -1.82 M 40818 1,2-dinitroxyethane -5.73 M 21075956 1,2-dinitroxypropane -4.95 M 7560 fenuron -9.13 M 17190 1,4,5,8-tetramino-anthraquinone -8.94 S1 20419 1-amino-4-anilino-anthraquinone -7.44 S1 12896 4-amino-4’-nitroazobenzene -11.24 S1 2566 carbofuran -9.61 M 6950 dinoseb -6.23 S1 81226 nitroxyacetone -5.99 M 85254 2-(nitrooxy)ethan-1-ol -8.18 M 31645 pirimor -9.41 M 6129 naphthalen-1-yl N-methylcarbamate -9.45 M 2078 alachlor -8.21 M 20848 nitralin -7.98 M 13263 2-N-ethyl-6-(methylsulfanyl)-4-N-(propan-2-yl)-1,3,5-triazine-2,4-diamine -7.65 M 13450 terbutryn -6.68 M 8606 captan -9.01 M 4929 prometryn -8.43 S1 4933 N-(3,4-dichlorophenyl)propanimidic acid -7.78 M 22188 terbacil -11.14 M 9570071 aldicarb -9.84 M 9595287 oxamyl -10.18 S1 4109 methomyl -10.65 S1 5216 simazine -10.22 M 795 imidazole -9.63 M 84179 N,N-4-trimethylbenzamide -9.76 M 81713 4-methoxy-N,N-dimethyl-benzamide -11.01 M 7240 2-chloroaniline -4.91 M 7812 4-chloroaniline -5.90 M 7932 3-chloroaniline -5.82 M 7977 2-chloropyridine -4.39 M 12287 3-chloropyridine -4.01 M 6342 acetonitrile -3.88 M 7854 propanenitrile -3.84 M 8008 butanenitrile -3.64 M 8061 pentanenitrile -3.52 M 7505 benzonitrile -4.10 M 6329 methanamine -4.55 M 6341 ethanamine -4.50 M 7852 propan-1-amine -4.39 M 7965 cyclohexanamine -4.59 M 17

Table 21 – continued from previous page PubChem ID Solute Name ∆GExp Remark 8007 butan-1-amine -4.24 M 8060 pentan-1-amine -4.09 M 8102 hexan-1-amine -3.95 M 8127 heptan-1-amine -3.79 M 8143 octan-1-amine -3.65 M 3301 1,2-Ethanediamine -7.60 G 674 N-methylmethanamine -4.29 M 7912 N-isopropylpropan-2-amine -3.22 M 8021 N-ethylethanamine -4.07 M 8148 N-butylbutan-1-amine -3.24 M 8902 N-propylpropan-1-amine -3.65 M 9033 Aziridine -5.42 G 10422 azetidine -5.56 M 14276 Octahydroazocine -4.40 T 31268 pyrrolidine -5.48 M 4837 piperazine -7.40 M 7515 N-methylaniline -4.69 M 1146 N,N-dimethylmethanamine -3.20 M 8454 1-Methylpyrrolidine -3.98 G 8471 N,N-diethylethanamine -3.22 M 12291 1-methylpiperidine -3.88 M 7818 1,4-dimethylpiperazine -7.58 M 13238893 N-methyl-N-(2,2,2-triﬂuoroethyl)aniline -1.92 M 4101 Methenamine -4.56 K 949 N,N-dimethylaniline -3.45 M 6115 aniline -5.49 M 6896 2,6-dimethylaniline -5.21 M 7057 naphthalen-2-amine -7.47 M 7242 2-methylaniline -5.53 M 7813 4-methylaniline -5.57 M 8640 naphthalen-1-amine -7.28 M 53167 1-methylpiperazine -7.77 M 1049 pyridine -4.69 M 6736 3-methyl-1H-indole -5.88 M 7047 quinoline -5.72 M 7304 1-methylpyrrole -2.89 M 7523 2-ethylpyridine -4.33 M 7936 2,4-dimethylpyridine -4.86 M 7937 2,6-dimethylpyridine -4.59 M 7963 4-methylpyridine -4.93 M 7970 3-methylpyridine -4.77 M 7975 2-methylpyridine -4.63 M 8027 pyrrole -4.78 M 10822 4-ethylpyridine -4.73 M 10823 3-ethylpyridine -4.59 M 11417 3,4-dimethylpyridine -5.22 M 11420 2,3-dimethylpyridine -4.82 M 11526 2,5-dimethylpyridine -4.72 M 11565 3,5-dimethylpyridine -4.84 M 19878 4-1,1-Dimethylethyl pyridine -4.46 G 68510 2,6-Bis 1,1-Dimethylethyl-pyridine -0.41 G 79 pyridine-3-carbonitrile -6.75 M 7506 pyridine-4-carbonitrile -6.02 M 447907 n-propyl-guanidine -10.91 K 69689 9-methyl-adenine -13.60 K 7976 2-methylpyrazine -5.51 M 26331 2-ethylpyrazine -5.45 M 34591 2-isobutylpyrazine -5.04 M 18

Table 21 – continued from previous page PubChem ID Solute Name ∆GExp Remark 1390 1-methylimidazole -8.41 M 12009 1-methyl-uracil -14.00 G 398 2-nitropropane -3.13 M 6375 nitromethane -4.02 M 6587 1-nitroethane -3.71 M 7903 1-nitropropane -3.34 M 12302 1-nitrobutane -3.09 M 220639 1-nitropentane -2.82 M 6944 1-methyl-2-nitro-benzene -3.58 M 7416 nitrobenzene -4.12 M 7422 1-methyl-3-nitro-benzene -3.45 M 178 acetamide -9.71 M 6578 propionamide -9.40 M 12332 hexanamide -9.31 M 2331 benzamide -11.00 M 6582 N-methylacetamide -10.00 M 77650 1-pyrrolidin-1-ylethanone -9.80 M 144381 3,3,3-trimethoxypropanenitrile -6.40 M 79143 1-methyl-cytosine -18.40 G 6228 N,N-dimethylformamide -7.81 M 10371 pyridine-3-carbaldehyde -7.10 M 13389 pyridine-4-carbaldehyde -7.00 M 79639 9-methyl-guanine -22.40 G 138975 N,N-dimethyl-4-nitro-benzamide -11.95 M 9589 1-(3-pyridyl)ethanone -8.26 M 14282 1-(4-pyridyl)ethanone -7.62 M 6946 2-nitroaniline -7.37 M 7423 3-nitroaniline -8.84 M 7475 4-nitroaniline -9.82 M 1672 3-Methoxy-1-propanamine -6.93 G 8018 2-methoxyethanamine -6.55 M 7000 2-methoxyaniline -6.12 M 7732 4-methoxyaniline -7.48 M 10824 3-methoxyaniline -7.29 M 8083 morpholine -7.17 M 12083 methyl 4-nitrobenzoate -6.88 M 7972 4-methylmorpholine -6.32 M 13019 4-hydroxybenzonitrile -10.17 M 13394 3-hydroxybenzonitrile -9.65 M 980 4-nitrophenol -10.64 M 6947 2-nitrophenol -4.58 M 11137 3-nitrophenol -9.62 M 32594 2-2-Methylpropyl-3-methoxy-pyrazine -3.68 K 33135 2-Ethyl-3-methoxypyrazine -4.40 K 688400 2-[(1R)-1-methylpropyl]-4,6-dinitro-phenolate -6.23 M 53479 2-chlorosyringaldehyde -7.78 M 53476 2,6-dichlorosyringaldehyde -8.68 M 7258 3,4-dichlorophenol -7.29 M 93462 3,5-dichloro-2,6-dimethoxyphenol -6.44 M 37207 1-chlorodibenzo-p-dioxin -3.52 M 38252 2-chlorodibenzo-p-dioxin -3.10 M 34586 2,3-dichlorodibenzo-p-dioxin -3.56 M 36613 2,7-dichlorodibenzo-p-dioxin -3.67 M 38253 1,2,4-trichlorodibenzo-p-dioxin -4.05 M 15625 2,3,7,8-tetrachlorodibenzo-p-dioxin -3.37 M 35454 1,2,3,4-tetrachlorodibenzo-p-dioxin -3.81 M 48889 1,2,3,7-tetrachlorodibenzo-p-dioxin -3.84 M 38251 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin -3.71 M 19

Table 21 – continued from previous page PubChem ID Solute Name ∆GExp Remark 38254 1,2,3,4,7-pentachlorodibenzo-p-dioxin -4.15 M 12309460 endosulfan alpha -4.23 M 3030 dicamba -9.86 M 3048 endrin -4.82 M 46174049 endrin -4.82 S1 144702 2-chloro-1,1,1-trimethoxy-ethane -4.59 M 7295 methyl 2-chloroacetate -4.00 M 1732 4-chloro-3-methyl-phenol -6.79 M 4684 4-chlorophenol -7.03 M 7245 2-chlorophenol -4.55 M 7933 3-chlorophenol -6.62 M 6214 hexachloroethane -0.64 M 12418 1,1,1,2-tetrachloroethane -1.43 M 6419 1,1,1,2,2-pentachloroethane -1.23 M 6337 chloroethane -0.63 M 11 1,2-dichloroethane -1.79 M 6365 1,1-dichloroethane -0.84 M 6574 1,1,2-trichloroethane -1.99 M 6591 1,1,2,2-tetrachloroethane -2.37 M 249266 1-chloro-2-phenyl-benzene -2.69 M 36980 1,4-dichloro-2-phenyl-benzene -2.46 M 37247 1,3,5-trichloro-2-phenyl-benzene -2.16 M 27588 1,3-dichloro-2-(2,6-dichlorophenyl)benzene -2.28 M 36401 1,2,3,4-tetrachloro-5-phenyl-benzene -3.48 M 63088 1,2,3-trichloro-5-(2,5-dichlorophenyl)benzene -3.61 M 91662 1,3,5-trichloro-2-(2,6-dichlorophenyl)benzene -1.96 M 38019 1,2,3,4-tetrachloro-5-(3,4-dichlorophenyl)benzene -3.04 M 63079 1,2,4,5-tetrachloro-3-(3,4-dichlorophenyl)benzene -4.38 M 37037 1,2,3,4-tetrachloro-5-(2,3,4-trichlorophenyl)benzene -4.40 M 38306 1,2,3,4-tetrachloro-5-(3,4,5-trichlorophenyl)benzene -3.17 M 39253 1,2,3,4-tetrachloro-5-(2,3,4,6-tetrachlorophenyl)benzene -4.61 M 6278 1,1,1-trichloroethane -0.19 M 16318 1,2,3,4,5-pentachloro-6-(2,3,4,5,6-pentachlorophenyl)benzene -2.98 M 18636 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin -4.53 M 8370 hexachlorobenzene -2.33 M 6720 pentachloronitrobenzene -5.22 M 3589 heptachlor -2.55 M 5993 chlordane -3.44 M 727 lindane -5.44 S1 6423 trichloro(nitro)methane -1.45 M 7503 benzyl chloride -1.93 M 8115 1-chloro-2-(2-chloroethoxy)ethane -4.23 M 10461 1,1-Thiobis(2-Chloroethane) -3.92 G 6327 chloromethane -0.55 M 6361 2-chloropropane -0.25 M 6563 2-chlorobutane 0.00 M 8005 1-chlorobutane -0.16 M 10486 2-chloro-2-methyl-propane 1.09 M 10899 1-chloropropane -0.33 M 10977 1-CHLOROPENTANE -0.07 M 10992 1-chlorohexane 0.00 M 12016 3-Chloropentane 0.04 G 12245 2-Chloropentane 0.07 G 6372 chloro-diﬂuoro-methane -0.50 M 11643 chloro-ﬂuoro-methane -0.77 M 12371 1-chloroheptane 0.29 M 6344 dichloromethane -1.31 M 6564 1,2-dichloropropane -1.27 M 20

Table 21 – continued from previous page PubChem ID Solute Name ∆GExp Remark 8059 1,4-dichlorobutane -2.32 M 8881 1,3-dichloropropane -1.89 M 10926 1,1-Dichlorobutane -0.70 G 221525 1,4-dichloropentane -2.32 G 6845 Acetic acid methyl ester -3.32 G 7238 1-chloro-2-methyl-benzene -1.14 M 7964 chlorobenzene -1.12 M 4685 1,4-dichlorobenzene -1.01 M 7239 1,2-dichlorobenzene -1.36 M 10943 1,3-dichlorobenzene -0.98 M 13 1,2,4-trichlorobenzene -1.12 M 6895 1,2,3-trichlorobenzene -1.24 M 7950 1,3,5-trichlorobenzene -0.78 M 7270 1,2,4,5-tetrachlorobenzene -1.34 M 12463 1,2,3,4-tetrachlorobenzene -1.34 M 12468 1,2,3,5-tetrachlorobenzene -1.62 M 7850 3-chloroprop-1-ene -0.57 M 6575 1,1,2-trichloroethylene -0.44 M 6212 chloroform -1.08 M 6366 1,1-dichloroethylene 0.25 M 638186 (E)-1,2-dichloroethylene -0.78 M 643833 (Z)-1,2-dichloroethylene -1.17 M 6338 chloroethylene -0.59 M 5943 carbon tetrachloride 0.08 M 6428 1,1,2-trichloro-1,2,2-trifluoro-ethane 1.77 M 6427 1,1,2,2-Tetrachloro-1,2-difluoroethane 0.82 G 6430 Chloropentafluoroethane 2.87 G 6391 Dichlorodifluoromethane 1.69 G 6429 1,2-Dichloro-1,1,2,2-tetrafluoroethane 2.32 G 9775 1,1-Dichlorotetrafluoroethane 2.51 G 6408 2-chloro-1,1,1-trifluoro-ethane 0.06 M 6392 Chlorotrifluoromethane 2.52 G 11095291 2-chloro-2-(difluoromethoxy)-1,1,1-trifluoro-ethane 0.10 M 4116 2,2-dichloro-1,1-difluoro-1-methoxy-ethane -1.12 M 31373 1,1,2,2-tetrachloroethylene 0.10 M 9609 ethylsulfanylethane -1.46 M 7498 benzyl bromide -2.38 M 402 hydrogen sulfide -0.70 M 878 methanethiol -1.20 M 6343 ethanethiol -1.14 M 7848 propanethiol -1.10 M 8012 butane-1-thiol -0.99 M 1068 methylsulfanylmethane -1.61 M 8118 1-propylsulfanylpropane -1.28 M 12264 2-isopropylsulfanylpropane -1.21 M 7520 methylsulfanylbenzene -2.73 M 8030 thiophene -1.40 M 11126 2-methylthiophene -1.38 M 12321 1,1-Thiobisethene -1.43 G 8077 ethyldisulfanylethane -1.64 M 12232 methyldisulfanylmethane -1.83 M 31347 sulfolane -8.61 M 3286 ethion -6.10 M 4004 malathion -8.15 S1 4790 phorate -4.37 M 25146 dialifor -5.74 M 13081 carbophenothion -6.50 M 2730 chlorpyrifos -5.04 M 21

Table 21 – continued from previous page PubChem ID Solute Name ∆GExp Remark 5853 trichlorfon -12.74 S1 5377791 chlorfenvinphos -7.07 S1 2268 azinphosmethyl -10.03 M 991 parathion -6.74 M 4130 methyparathion -7.19 M 3017 diazinon -6.48 M 9321 hydrazine -9.30 M 222 ammonia -4.29 M 31297 methanesulfonyl chloride -4.87 M 6213 methylsulfonylmethane -10.08 M 4156 methyl methanesulfonate -4.87 M 6497 dimethyl sulfate -5.10 M 679 methylsulﬁnylmethane -9.28 M 22

exp pred Table S10: The experimental and predicted solvation free energy for the SAMPL 2 test set. ∆G is the experimental solvation free energy, ∆GAM1−BCC, pred pred pred ∆GMulliken, ∆GGasteiger, and ∆GSIESTA are the predicted solvation free energy with four different types of charges. The Amber bondi force field are employed for the atomic radius parametrization. The energy data are all in the unit of kcal/mol. exp pred pred pred pred Solute Name ∆G ∆GAM1−BCC ∆GMulliken ∆GGasteiger ∆GSIESTA (+-)ibuprofen -7.00 -7.71 -10.96 -9.25 -7.03 glycerol -13.43 -14.62 -13.10 -14.40 -13.22 hexachloroethane -0.64 -1.24 -1.87 -0.39 -1.01 hexachlorobenzene -2.33 -0.34 -1.40 -3.19 -3.22 Trimethyl phosphate -8.70 -9.00 -3.30 -3.96 -7.27 phthalimide -9.61 -10.87 -9.63 -10.30 -10.31 pentachloronitrobenzene -5.22 -0.68 -2.29 -6.52 -8.04 caffeine -12.64 -14.15 -13.41 -10.31 -12.60 Ketoprofen -10.78 -12.71 -14.17 -11.35 -9.53 Flurbiprofen -8.42 -3.52 -5.90 -3.38 -3.77 naproxen -10.21 -11.90 -12.43 -9.76 -9.39 diflunisal -9.40 -11.30 -9.55 -11.23 -11.07 acetylsalicylic acid -9.94 -10.33 -10.46 -9.03 -8.01 octafluorocyclobutane 3.43 5.47 4.57 5.30 3.86 Uracil -16.59 -16.84 -13.14 -11.37 -14.57 5-fluorouracil -16.92 -17.46 -12.22 -11.39 -14.72 5-chlorouracil -17.74 -16.91 -10.17 -4.21 -14.36 6-chlorouracil -15.83 -15.35 -9.30 -5.15 -14.44 5-trifluoromethyluracil -15.46 -18.76 -8.82 -5.16 -11.67 cyanuric acid -18.06 -20.74 -13.99 -11.38 -17.59 D-xylose -20.52 -17.11 -19.44 -18.48 -17.99 D-glucose -25.47 -23.50 -24.00 -25.33 -24.40 1,1,1-trifluoro-2,2,2-trimethoxyethane -0.80 -0.63 -2.30 -1.79 -2.34 propyl paraben -9.37 -8.08 -6.17 -6.92 -7.70 butyl paraben -8.72 -8.42 -6.43 -6.96 -7.33 methyl paraben -9.51 -8.82 -6.61 -7.48 -7.85 ethyl paraben -9.20 -8.56 -6.43 -7.13 -7.55 sulfolane -8.61 -8.73 -11.37 -8.47 -10.17 5-bromouracil -18.17 -15.61 -12.69 -11.29 NA RMSE 1.95 (1.97) 3.38 (3.47) 4.62 (4.72) 1.90 (NA) ME -0.17 (-0.26) 1.55 (1.69) 2.45 (2.61) 0.87 (NA) 23

exp pred Table S11: The experimental and predicted solvation free energy for the SAMPL 2 test set. ∆G is the experimental solvation free energy, ∆GAM1−BCC, pred pred pred ∆GMulliken, ∆GGasteiger, and ∆GSIESTA are the predicted solvation free energy with four different types of charges. The Amber mbondi2 force field are employed for the atomic radius parametrization. The energy data are all in the unit of kcal/mol. exp pred pred pred pred Solute Name ∆G ∆GAM1−BCC ∆GMulliken ∆GGasteiger ∆GSIESTA (+-)ibuprofen -7.00 -7.71 -10.96 -9.25 -7.03 glycerol -13.43 -14.62 -13.10 -14.40 -13.22 hexachloroethane -0.64 -1.24 -1.87 -0.39 -1.00 hexachlorobenzene -2.33 -0.34 -1.40 -3.19 -3.18 Trimethyl phosphate -8.70 -9.00 -3.30 -3.96 -7.27 phthalimide -9.61 -10.87 -9.65 -10.32 -10.11 pentachloronitrobenzene -5.22 -0.68 -2.29 -6.52 -7.93 caffeine -12.64 -14.32 -13.50 -10.30 -12.77 Ketoprofen -10.78 -12.71 -14.17 -11.35 -9.53 Flurbiprofen -8.42 -3.52 -5.90 -3.38 -3.77 naproxen -10.21 -11.90 -12.43 -9.76 -9.39 diflunisal -9.40 -11.30 -9.55 -11.23 -11.07 acetylsalicylic acid -9.94 -10.33 -10.46 -9.03 -8.01 octafluorocyclobutane 3.43 5.47 4.57 5.30 3.86 Uracil -16.59 -16.39 -12.89 -11.36 -13.70 5-fluorouracil -16.92 -16.85 -11.89 -11.32 -13.52 5-chlorouracil -17.74 -15.79 -9.49 -4.00 -12.48 6-chlorouracil -15.83 -14.32 -8.71 -4.95 -12.73 5-trifluoromethyluracil -15.46 -17.98 -8.39 -5.06 -10.22 cyanuric acid -18.06 -19.32 -13.63 -11.82 -15.41 D-xylose -20.52 -17.11 -19.44 -18.48 -17.99 D-glucose -25.47 -23.50 -24.00 -25.33 -24.40 1,1,1-trifluoro-2,2,2-trimethoxyethane -0.80 -0.63 -2.30 -1.79 -2.34 propyl paraben -9.37 -8.08 -6.17 -6.92 -7.70 butyl paraben -8.72 -8.42 -6.43 -6.96 -7.33 methyl paraben -9.51 -8.82 -6.61 -7.48 -7.85 ethyl paraben -9.20 -8.56 -6.43 -7.13 -7.55 sulfolane -8.61 -8.73 -11.37 -8.47 -10.17 5-bromouracil -18.17 -15.02 -12.13 -10.90 NA RMSE 1.90 (1.96) 3.55 (3.66) 4.65 (4.76) 2.35 (NA) ME -0.36 (-0.46) 2.46 (2.62) 1.64 (1.79) 1.21 (NA) 24

exp pred Table S12: The experimental and predicted solvation free energy for the SAMPL 2 test set. ∆G is the experimental solvation free energy, ∆GAM1−BCC, pred pred pred ∆GMulliken, ∆GGasteiger, and ∆GSIESTA are the predicted solvation free energy with four different types of charges. The ZAP9 force field are employed for the atomic radius parametrization. The energy data are all in the unit of kcal/mol. exp pred pred pred pred Solute Name ∆G ∆GAM1−BCC ∆GMulliken ∆GGasteiger ∆GSIESTA (+-)ibuprofen -7.00 -8.88 -10.41 -8.36 -6.06 glycerol -13.43 -14.05 -13.27 -14.32 -13.87 hexachloroethane -0.64 -0.92 -1.56 -0.58 -1.29 hexachlorobenzene -2.33 -0.08 -1.15 -2.87 -0.82 Trimethyl phosphate -8.70 -6.85 -3.30 -3.66 -7.85 phthalimide -9.61 -10.48 -10.60 -11.23 -9.75 pentachloronitrobenzene -5.22 -0.70 -1.90 -5.40 -3.16 caffeine -12.64 -13.12 -13.12 -10.78 -11.18 Ketoprofen -10.78 -13.98 -14.16 -10.85 -7.80 Flurbiprofen -8.42 -3.93 -5.66 -3.72 -4.73 naproxen -10.21 -13.04 -12.54 -9.28 -8.46 diflunisal -9.40 -12.59 -10.32 -10.31 -11.86 acetylsalicylic acid -9.94 -10.80 -10.44 -8.70 -7.38 octafluorocyclobutane 3.43 3.81 3.49 3.12 3.32 Uracil -16.59 -16.43 -14.02 -12.37 -14.56 5-fluorouracil -16.92 -17.66 -12.88 -10.74 -14.00 5-chlorouracil -17.74 -15.10 -9.53 -3.86 -13.83 6-chlorouracil -15.83 -13.54 -8.88 -4.86 -14.09 5-trifluoromethyluracil -15.46 -16.97 -9.81 -5.48 -13.25 cyanuric acid -18.06 -19.16 -15.64 -13.05 -17.07 D-xylose -20.52 -17.24 -19.75 -18.87 -18.27 D-glucose -25.47 -23.57 -24.11 -25.45 -24.73 1,1,1-trifluoro-2,2,2-trimethoxyethane -0.80 -0.83 -1.08 -1.33 -2.68 propyl paraben -9.37 -7.93 -6.48 -6.86 -8.05 butyl paraben -8.72 -8.32 -6.75 -6.84 -7.32 methyl paraben -9.51 -8.46 -6.81 -7.08 -8.09 ethyl paraben -9.20 -8.31 -6.68 -6.94 -8.81 sulfolane -8.61 -8.10 -7.76 -11.02 -10.48 5-bromouracil -18.17 -16.88 -18.69 -15.54 NA RMSE 2.05 (2.03) 3.19 (3.15) 4.56 (4.51) 1.93 (NA) ME -0.37 (-0.41) 2.36 (2.37) 1.52 (1.45) 1.13 (NA) 25

exp pred Table S13: The experimental and predicted solvation free energy for the SAMPL 3 test set. ∆G is the experimental solvation free energy, ∆GAM1−BCC, pred pred pred ∆GMulliken, ∆GGasteiger, and ∆GSIESTA are the predicted solvation free energy with four different types of charges. The Amber6 force ﬁeld are employed for the atomic radius parametrization. The energy data are all in the unit of kcal/mol. exp pred pred pred pred Solute Name ∆G ∆GAM1−BCC ∆GMulliken ∆GGasteiger ∆GSIESTA dibenzo-p-dioxin -3.15 -2.04 -3.76 -2.66 -4.13 ethane 1.83 1.34 1.48 1.20 1.15 biphenyl -2.70 -2.49 -2.02 -2.76 -2.36 1,1,1,2-tetrachloroethane -1.43 -2.84 -2.40 -1.28 -0.70 1,1,1,2,2-pentachloroethane -1.23 -2.83 -2.58 -1.39 -1.08 hexachloroethane -0.64 -0.64 -0.64 -0.64 -0.64 chloroethane -0.63 -0.70 -0.42 -0.25 -0.17 1,2-dichloroethane -1.79 -3.11 -2.07 -1.44 -2.24 1,1-dichloroethane -0.84 -1.80 -1.35 -0.65 -0.36 1,1,2-trichloroethane -1.99 -3.82 -2.72 -2.01 -1.79 1,1,2,2-tetrachloroethane -2.37 -3.90 -2.89 -2.05 -0.92 1,2,3,4,5-pentachloro-6-(2,3,4,5,6-pentachlorophenyl)benzene -2.98 -1.88 -3.38 -5.85 -2.85 1-chloro-2-phenyl-benzene -2.69 -2.15 -1.53 -2.00 -1.47 1,4-dichloro-2-phenyl-benzene -2.46 -2.00 -1.64 -2.12 -1.23 1,3,5-trichloro-2-phenyl-benzene -2.16 -1.87 -1.78 -2.53 -1.36 1,3-dichloro-2-(2,6-dichlorophenyl)benzene -2.28 -3.28 -3.39 -2.66 -0.82 1,2,3,4-tetrachloro-5-phenyl-benzene -3.48 -1.61 -1.84 -3.06 -1.33 1,2,3-trichloro-5-(2,5-dichlorophenyl)benzene -3.61 -2.11 -2.31 -2.92 -2.11 1,3,5-trichloro-2-(2,6-dichlorophenyl)benzene -1.96 -2.81 -3.23 -2.85 -1.06 1,2,3,4-tetrachloro-5-(3,4-dichlorophenyl)benzene -3.04 -2.15 -2.46 -3.71 -2.89 1,2,4,5-tetrachloro-3-(3,4-dichlorophenyl)benzene -4.38 -2.32 -2.63 -3.69 -2.79 1,2,3,4-tetrachloro-5-(2,3,4-trichlorophenyl)benzene -4.40 -2.46 -3.01 -4.21 -1.88 1,2,3,4-tetrachloro-5-(3,4,5-trichlorophenyl)benzene -3.17 -2.02 -2.45 -4.24 -1.79 1,2,3,4-tetrachloro-5-(2,3,4,6-tetrachlorophenyl)benzene -4.61 -2.26 -3.09 -4.61 -3.54 1,1,1-trichloroethane -0.19 -1.64 -1.61 -0.44 -0.06 1-chlorodibenzo-p-dioxin -3.52 -2.82 -2.03 -3.02 -3.11 2-chlorodibenzo-p-dioxin -3.10 -2.28 -1.80 -2.81 -3.17 2,3-dichlorodibenzo-p-dioxin -3.56 -2.13 -1.71 -3.18 -3.65 2,7-dichlorodibenzo-p-dioxin -3.67 -2.22 -1.70 -3.04 -3.20 1,2,4-trichlorodibenzo-p-dioxin -4.05 -2.79 -1.84 -4.04 -4.06 2,3,7,8-tetrachlorodibenzo-p-dioxin -3.37 -2.13 -1.53 -3.96 -4.39 1,2,3,4-tetrachlorodibenzo-p-dioxin -3.81 -2.57 -1.78 -4.79 -4.46 1,2,3,7-tetrachlorodibenzo-p-dioxin -3.84 -2.43 -1.67 -4.24 -4.31 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin -3.71 -2.62 -1.53 -5.75 -5.49 1,2,3,4,7-pentachlorodibenzo-p-dioxin -4.15 -2.61 -1.64 -5.17 -5.33 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin -4.53 -3.21 -1.57 -7.88 -6.66 RMSE 1.28 1.42 0.97 1.08 ME 0.38 0.72 -0.16 0.34 26

exp pred Table S14: The experimental and predicted solvation free energy for the SAMPL 3 test set. ∆G is the experimental solvation free energy, ∆GAM1−BCC, pred pred pred0 ∆GMulliken, ∆GGasteiger, and ∆GSIESTA are the predicted solvation free energy with four different types of charges. The Amber bondi force ﬁeld are employed for the atomic radius parametrization. The energy data are all in the unit of kcal/mol. exp pred pred pred pred Solute Name ∆G ∆GAM1−BCC ∆GMulliken ∆GGasteiger ∆GSIESTA dibenzo-p-dioxin -3.15 -2.88 -3.68 -2.49 -4.26 ethane 1.83 1.35 1.49 1.03 1.23 biphenyl -2.70 -2.56 -2.07 -2.71 -2.79 1,1,1,2-tetrachloroethane -1.43 -2.94 -2.50 -1.37 -1.06 1,1,1,2,2-pentachloroethane -1.23 -2.85 -2.61 -1.49 -1.39 hexachloroethane -0.64 -0.64 -0.64 -0.64 -0.64 chloroethane -0.63 -0.75 -0.43 -0.32 -0.40 1,2-dichloroethane -1.79 -3.29 -2.21 -1.55 -3.04 1,1-dichloroethane -0.84 -1.90 -1.39 -0.75 -0.81 1,1,2-trichloroethane -1.99 -4.05 -2.88 -2.18 -2.24 1,1,2,2-tetrachloroethane -2.37 -4.12 -3.03 -2.23 -1.86 1,2,3,4,5-pentachloro-6-(2,3,4,5,6-pentachlorophenyl)benzene -2.98 -1.03 -2.63 -5.65 -1.59 1-chloro-2-phenyl-benzene -2.69 -2.19 -1.52 -1.92 -1.91 1,4-dichloro-2-phenyl-benzene -2.46 -1.99 -1.56 -2.05 -1.76 1,3,5-trichloro-2-phenyl-benzene -2.16 -1.82 -1.71 -2.44 -1.76 1,3-dichloro-2-(2,6-dichlorophenyl)benzene -2.28 -3.18 -3.26 -2.59 -0.62 1,2,3,4-tetrachloro-5-phenyl-benzene -3.48 -1.39 -1.59 -2.94 -1.88 1,2,3-trichloro-5-(2,5-dichlorophenyl)benzene -3.61 -1.95 -2.12 -2.81 -2.03 1,3,5-trichloro-2-(2,6-dichlorophenyl)benzene -1.96 -2.67 -3.08 -2.77 -0.78 1,2,3,4-tetrachloro-5-(3,4-dichlorophenyl)benzene -3.04 -1.85 -2.15 -3.58 -1.56 1,2,4,5-tetrachloro-3-(3,4-dichlorophenyl)benzene -4.38 -2.05 -2.37 -3.57 -1.67 1,2,3,4-tetrachloro-5-(2,3,4-trichlorophenyl)benzene -4.40 -2.05 -2.60 -4.05 -1.08 1,2,3,4-tetrachloro-5-(3,4,5-trichlorophenyl)benzene -3.17 -1.62 -2.06 -4.09 -1.10 1,2,3,4-tetrachloro-5-(2,3,4,6-tetrachlorophenyl)benzene -4.61 -1.76 -2.63 -4.46 -2.69 1,1,1-trichloroethane -0.19 -1.65 -1.59 -0.50 -0.12 1-chlorodibenzo-p-dioxin -3.52 -2.84 -2.04 -2.73 -2.97 2-chlorodibenzo-p-dioxin -3.10 -2.33 -1.84 -2.53 -3.23 2,3-dichlorodibenzo-p-dioxin -3.56 -2.08 -1.67 -2.80 -3.63 2,7-dichlorodibenzo-p-dioxin -3.67 -2.25 -1.73 -2.66 -3.31 1,2,4-trichlorodibenzo-p-dioxin -4.05 -2.63 -1.68 -3.59 -3.68 2,3,7,8-tetrachlorodibenzo-p-dioxin -3.37 -1.97 -1.42 -3.40 -4.16 1,2,3,4-tetrachlorodibenzo-p-dioxin -3.81 -2.28 -1.51 -4.25 -3.97 1,2,3,7-tetrachlorodibenzo-p-dioxin -3.84 -2.24 -1.51 -3.69 -3.95 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin -3.71 -2.19 -1.16 -5.04 -4.73 1,2,3,4,7-pentachlorodibenzo-p-dioxin -4.15 -2.26 -1.31 -4.54 -4.77 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin -4.53 -2.41 -0.85 -6.97 -5.45 RMSE 1.47 1.58 0.82 1.16 ME -0.56 0.85 -0.09 0.45 27

exp pred Table S15: The experimental and predicted solvation free energy for the SAMPL 3 test set. ∆G is the experimental solvation free energy, ∆GAM1−BCC, pred pred pred ∆GMulliken, ∆GGasteiger, and ∆GSIESTA are the predicted solvation free energy with four different types of charges. The Amber mbondi2 force ﬁeld are employed for the atomic radius parametrization. The energy data are all in the unit of kcal/mol. exp pred pred pred pred Solute Name ∆G ∆GAM1−BCC ∆GMulliken ∆GGasteiger ∆GSIESTA dibenzo-p-dioxin -3.15 -2.88 -3.68 -2.49 -4.26 ethane 1.83 1.35 1.49 1.03 1.23 biphenyl -2.70 -2.56 -2.07 -2.71 -2.79 1,1,1,2-tetrachloroethane -1.43 -2.94 -2.50 -1.37 -1.06 1,1,1,2,2-pentachloroethane -1.23 -2.85 -2.61 -1.49 -1.39 hexachloroethane -0.64 -0.64 -0.64 -0.64 -0.64 chloroethane -0.63 -0.75 -0.43 -0.32 -0.40 1,2-dichloroethane -1.79 -3.29 -2.21 -1.55 -3.04 1,1-dichloroethane -0.84 -1.90 -1.39 -0.75 -0.81 1,1,2-trichloroethane -1.99 -4.05 -2.88 -2.18 -2.24 1,1,2,2-tetrachloroethane -2.37 -4.12 -3.03 -2.23 -1.86 1,2,3,4,5-pentachloro-6-(2,3,4,5,6-pentachlorophenyl)benzene -2.98 -1.03 -2.63 -5.65 -1.59 1-chloro-2-phenyl-benzene -2.69 -2.19 -1.52 -1.92 -1.91 1,4-dichloro-2-phenyl-benzene -2.46 -1.99 -1.56 -2.05 -1.76 1,3,5-trichloro-2-phenyl-benzene -2.16 -1.82 -1.71 -2.44 -1.76 1,3-dichloro-2-(2,6-dichlorophenyl)benzene -2.28 -3.18 -3.26 -2.59 -0.62 1,2,3,4-tetrachloro-5-phenyl-benzene -3.48 -1.39 -1.59 -2.94 -1.88 1,2,3-trichloro-5-(2,5-dichlorophenyl)benzene -3.61 -1.95 -2.12 -2.81 -2.03 1,3,5-trichloro-2-(2,6-dichlorophenyl)benzene -1.96 -2.67 -3.08 -2.77 -0.78 1,2,3,4-tetrachloro-5-(3,4-dichlorophenyl)benzene -3.04 -1.85 -2.15 -3.58 -1.56 1,2,4,5-tetrachloro-3-(3,4-dichlorophenyl)benzene -4.38 -2.05 -2.37 -3.57 -1.67 1,2,3,4-tetrachloro-5-(2,3,4-trichlorophenyl)benzene -4.40 -2.05 -2.60 -4.05 -1.08 1,2,3,4-tetrachloro-5-(3,4,5-trichlorophenyl)benzene -3.17 -1.62 -2.06 -4.09 -1.10 1,2,3,4-tetrachloro-5-(2,3,4,6-tetrachlorophenyl)benzene -4.61 -1.76 -2.63 -4.46 -2.69 1,1,1-trichloroethane -0.19 -1.65 -1.59 -0.50 -0.12 1-chlorodibenzo-p-dioxin -3.52 -2.84 -2.04 -2.73 -2.97 2-chlorodibenzo-p-dioxin -3.10 -2.33 -1.84 -2.53 -3.23 2,3-dichlorodibenzo-p-dioxin -3.56 -2.08 -1.67 -2.80 -3.63 2,7-dichlorodibenzo-p-dioxin -3.67 -2.25 -1.73 -2.66 -3.31 1,2,4-trichlorodibenzo-p-dioxin -4.05 -2.63 -1.68 -3.59 -3.68 2,3,7,8-tetrachlorodibenzo-p-dioxin -3.37 -1.97 -1.42 -3.40 -4.16 1,2,3,4-tetrachlorodibenzo-p-dioxin -3.81 -2.28 -1.51 -4.25 -3.97 1,2,3,7-tetrachlorodibenzo-p-dioxin -3.84 -2.24 -1.51 -3.69 -3.95 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin -3.71 -2.19 -1.16 -5.04 -4.73 1,2,3,4,7-pentachlorodibenzo-p-dioxin -4.15 -2.26 -1.31 -4.54 -4.77 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin -4.53 -2.41 -0.85 -6.97 -5.45 RMSE 1.47 1.58 0.82 1.16 ME -0.56 0.85 -0.09 0.39 28

exp pred Table S16: The experimental and predicted solvation free energy for the SAMPL 3 test set. ∆G is the experimental solvation free energy, ∆GAM1−BCC, pred pred pred ∆GMulliken, ∆GGasteiger, and ∆GSIESTA are the predicted solvation free energy with four different types of charges. The ZAP9 force ﬁeld are employed for the atomic radius parametrization. The energy data are all in the unit of kcal/mol. exp pred pred pred pred Solute Name ∆G ∆GAM1−BCC ∆GMulliken ∆GGasteiger ∆GSIESTA dibenzo-p-dioxin -3.15 -2.32 -4.31 -3.43 -4.23 ethane 1.83 1.29 1.41 1.00 1.35 biphenyl -2.70 -2.56 -2.14 -2.91 -2.79 1,1,1,2-tetrachloroethane -1.43 -2.72 -2.38 -1.49 -2.30 1,1,1,2,2-pentachloroethane -1.23 -2.60 -2.41 -1.68 -2.20 hexachloroethane -0.64 -0.64 -0.64 -0.64 -0.64 chloroethane -0.63 -0.64 -0.36 -0.35 -0.90 1,2-dichloroethane -1.79 -3.05 -2.10 -1.56 -4.88 1,1-dichloroethane -0.84 -1.78 -1.40 -0.79 -1.18 1,1,2-trichloroethane -1.99 -3.81 -2.77 -2.24 -3.32 1,1,2,2-tetrachloroethane -2.37 -3.92 -2.93 -2.37 -2.97 1,2,3,4,5-pentachloro-6-(2,3,4,5,6-pentachlorophenyl)benzene -2.98 -0.90 -2.47 -5.38 -3.45 1-chloro-2-phenyl-benzene -2.69 -2.15 -1.50 -1.94 -1.71 1,4-dichloro-2-phenyl-benzene -2.46 -2.10 -1.71 -2.10 -2.21 1,3,5-trichloro-2-phenyl-benzene -2.16 -1.97 -1.85 -2.48 -2.39 1,3-dichloro-2-(2,6-dichlorophenyl)benzene -2.28 -3.52 -3.39 -2.87 -3.14 1,2,3,4-tetrachloro-5-phenyl-benzene -3.48 -1.48 -1.67 -2.90 -2.98 1,2,3-trichloro-5-(2,5-dichlorophenyl)benzene -3.61 -2.31 -2.47 -2.90 -2.34 1,3,5-trichloro-2-(2,6-dichlorophenyl)benzene -1.96 -3.04 -3.30 -2.99 -3.29 1,2,3,4-tetrachloro-5-(3,4-dichlorophenyl)benzene -3.04 -2.15 -2.42 -3.62 -2.34 1,2,4,5-tetrachloro-3-(3,4-dichlorophenyl)benzene -4.38 -2.38 -2.66 -3.64 -2.82 1,2,3,4-tetrachloro-5-(2,3,4-trichlorophenyl)benzene -4.40 -2.32 -2.76 -4.11 -2.49 1,2,3,4-tetrachloro-5-(3,4,5-trichlorophenyl)benzene -3.17 -1.91 -2.33 -4.09 -2.49 1,2,3,4-tetrachloro-5-(2,3,4,6-tetrachlorophenyl)benzene -4.61 -1.95 -2.77 -4.45 -2.57 1,1,1-trichloroethane -0.19 -1.51 -1.57 -0.59 -1.10 1-chlorodibenzo-p-dioxin -3.52 -2.45 -2.90 -3.59 -1.94 2-chlorodibenzo-p-dioxin -3.10 -1.98 -2.82 -3.33 -1.77 2,3-dichlorodibenzo-p-dioxin -3.56 -1.77 -2.53 -3.51 -1.97 2,7-dichlorodibenzo-p-dioxin -3.67 -2.01 -2.69 -3.39 -1.92 1,2,4-trichlorodibenzo-p-dioxin -4.05 -2.21 -2.41 -4.20 -1.85 2,3,7,8-tetrachlorodibenzo-p-dioxin -3.37 -1.70 -2.25 -3.92 -2.37 1,2,3,4-tetrachlorodibenzo-p-dioxin -3.81 -1.74 -2.00 -4.67 -2.17 1,2,3,7-tetrachlorodibenzo-p-dioxin -3.84 -1.90 -2.24 -4.20 -1.87 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin -3.71 -1.66 -1.79 -5.25 -2.34 1,2,3,4,7-pentachlorodibenzo-p-dioxin -4.15 -1.75 -1.90 -4.87 -2.14 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin -4.53 -1.53 -1.15 -6.84 -2.69 RMSE 1.55 1.28 0.78 1.33 ME -0.68 -0.37 0.31 -0.59 29

exp pred Table S17: The experimental and predicted solvation free energy for the SAMPL 4 test set. ∆G is the experimental solvation free energy, ∆GAM1−BCC, pred pred pred ∆GMulliken, ∆GGasteiger, and ∆GSIESTA are the predicted solvation free energy with four different types of charges. The Amber 6 force ﬁeld are employed for the atomic radius parametrization. The energy data are all in the unit of kcal/mol. exp pred pred pred pred Solute Name ∆G ∆GAM1−BCC ∆GMulliken ∆GGasteiger ∆GSIESTA cyclohexene 0.14 1.07 0.87 1.15 1.29 1,1-diphenylethene -2.78 -2.78 -2.42 -2.08 -1.87 2-methylbenzaldehyde -3.93 -2.97 -4.41 -3.43 -3.80 hexyl acetate -2.26 -2.36 -2.52 -2.46 -2.55 (2S,5R)-2-isopropyl-5-methylcyclohexanone -2.53 -3.03 -3.03 -3.20 -3.12 piperidine -5.11 -3.72 -3.69 -3.77 -3.42 (1R,2S,5R)-2-isopropyl-5-methylcyclohexanol -3.20 -3.32 -3.61 -4.03 -3.70 (2R,3R,4R,5R)-Hexan-1,2,3,4,5,6-hexol -23.62 -29.50 -23.82 -21.93 -29.82 2-ethylphenol -5.66 -5.74 -5.75 -5.79 -6.10 tetrahydropyran -3.12 -2.12 -1.92 -2.32 -1.87 1,4-dioxane -5.06 -4.97 -4.45 -4.79 -4.75 diphenyl ether -2.87 -1.68 -2.33 -1.82 -2.84 1,2-dimethoxybenzene -5.33 -4.92 -4.58 -6.83 -4.38 dibenzo-p-dioxin -3.15 -2.04 -3.76 -2.66 -4.13 anthracene -3.95 -4.12 -3.68 -4.10 -3.91 1-ethyl-2-methylbenzene -0.85 -0.73 -0.97 -0.84 -0.70 9,10-dihydroanthracene -3.78 -3.23 -3.58 -3.08 -2.95 HEXYL NITRATE -1.66 -1.08 -1.29 -1.65 -2.24 3-nitrooxypropyl nitrate -4.80 -5.71 -5.69 -5.83 -5.58 1,3-bis-(nitrooxy)butane -4.29 -4.84 -5.09 -4.83 -5.03 4-(1-Methylethenyl)-1-cyclohexene-1-carboxaldehyde -4.09 -3.44 -3.08 -2.83 -3.34 2-hydroxybenzaldehyde -4.68 -4.80 -6.04 -4.80 -5.04 2-chlorosyringaldehyde -7.78 -8.58 -9.46 -9.41 -7.27 2,6-dichlorosyringaldehyde -8.68 -7.64 -8.77 -10.19 -7.79 2-(2,3-dimethylphenyl)aminobenzoic acid -6.78 -7.81 -8.43 -8.44 -6.23 (3R)-3,7-Dimethylocta-1,6-dien-3-yl acetate -2.49 -2.87 -2.38 -1.97 -2.84 2-ethoxyethyl acetate -5.31 -4.84 -4.78 -4.48 -5.38 1,4-diamino-9,10-anthracenedione -11.85 -11.81 -8.29 -10.18 -10.31 1-amino-9,10-anthracenedione -9.44 -9.38 -7.86 -8.97 -9.45 2-amino-9,10-anthraquinone -11.53 -11.34 -8.64 -8.76 -11.64 1-(2-hydroxyethylamino)-9,10-anthraquinone -14.21 -13.52 -13.37 -14.28 -13.33 1-amino-4-hydroxy-9,10-anthracenedione -9.53 -9.80 -8.61 -11.62 -9.43 (2R,5R)-2-methyl-5-(1-methylethenyl)-cyclohexanone -3.75 -3.32 -3.40 -2.78 -3.65 6-isopropyl-3-methyl-1-cyclohex-2-enone -4.51 -3.43 -3.52 -2.39 -3.75 Amitriptyline -7.43 -6.29 -4.93 -6.25 -3.90 [2-benzhydryloxyethyl]-dimethyl-amine -9.34 -10.01 -7.64 -8.97 -6.01 (1S,5R)-2-methyl-5-(1-methylethenyl)-2-cyclohexen-1-ol -4.44 -4.84 -5.39 -4.82 -4.70 (2E)-3,7-dimethylocta-2,6-dien-1-ol -4.45 -5.80 -6.21 -5.30 -6.02 (2Z)-3,7-dimethylocta-2,6-dien-1-ol -4.78 -2.98 -5.91 -5.00 -3.66 1-butoxy-2-propanol -5.73 -5.09 -6.05 -5.47 -4.08 3,4-dichlorophenol -7.29 -6.64 -5.65 -7.26 -9.19 2-methoxyphenol -5.94 -6.30 -5.82 -4.34 -5.87 4-methyl-2-methoxyphenol -5.80 -8.71 -6.55 -6.70 -6.55 4-propylguaiacol -5.26 -7.02 -6.05 -5.18 -5.40 2,6-dimethoxyphenol -6.96 -8.87 -7.03 -8.34 -7.68 3,5-dichloro-2,6-dimethoxyphenol -6.44 -6.83 -5.62 -7.31 -5.09 1-benzylimidazole -7.63 -9.50 -10.04 -7.91 -8.63 RMSE 1.28 1.20 1.08 1.41 ME -0.14 0.11 0.18 0.15 30

exp pred Table S18: The experimental and predicted solvation free energy for the SAMPL 4 test set. ∆G is the experimental solvation free energy, ∆GAM1−BCC, pred pred pred ∆GMulliken, ∆GGasteiger, and ∆GSIESTA are the predicted solvation free energy with four different types of charges. The Amber bondi force ﬁeld are employed for the atomic radius parametrization. The energy data are all in the unit of kcal/mol. exp pred pred pred pred Solute Name ∆G ∆GAM1−BCC ∆GMulliken ∆GGasteiger ∆GSIESTA cyclohexene 0.14 0.99 0.78 1.15 1.27 1,1-diphenylethene -2.78 -2.83 -2.39 -1.97 -1.58 2-methylbenzaldehyde -3.93 -2.92 -4.48 -3.35 -3.47 hexyl acetate -2.26 -2.45 -2.58 -2.44 -2.22 (2S,5R)-2-isopropyl-5-methylcyclohexanone -2.53 -2.95 -3.02 -3.23 -2.92 piperidine -5.11 -3.82 -3.79 -3.72 -3.33 (1R,2S,5R)-2-isopropyl-5-methylcyclohexanol -3.20 -3.59 -3.89 -4.15 -4.44 (2R,3R,4R,5R)-Hexan-1,2,3,4,5,6-hexol -23.62 -25.61 -22.46 -20.52 -24.15 2-ethylphenol -5.66 -5.61 -5.71 -5.75 -5.54 tetrahydropyran -3.12 -2.25 -2.10 -2.29 -1.78 1,4-dioxane -5.06 -5.12 -4.62 -4.97 -5.16 diphenyl ether -2.87 -1.72 -2.40 -1.52 -2.39 1,2-dimethoxybenzene -5.33 -4.89 -4.57 -6.68 -3.70 dibenzo-p-dioxin -3.15 -2.88 -3.68 -2.49 -4.26 anthracene -3.95 -4.11 -3.67 -3.96 -4.43 1-ethyl-2-methylbenzene -0.85 -0.69 -0.92 -0.88 -0.75 9,10-dihydroanthracene -3.78 -3.20 -3.58 -3.01 -4.63 HEXYL NITRATE -1.66 -1.08 -1.33 -1.65 -1.60 3-nitrooxypropyl nitrate -4.80 -5.73 -5.69 -5.85 -6.77 1,3-bis-(nitrooxy)butane -4.29 -4.83 -5.08 -4.80 -4.47 4-(1-Methylethenyl)-1-cyclohexene-1-carboxaldehyde -4.09 -4.32 -3.11 -2.77 -4.15 2-hydroxybenzaldehyde -4.68 -5.93 -7.66 -3.94 -7.05 2-chlorosyringaldehyde -7.78 -5.86 -9.67 -8.87 -9.31 2,6-dichlorosyringaldehyde -8.68 -9.17 -8.80 -9.60 -9.06 2-(2,3-dimethylphenyl)aminobenzoic acid -6.78 -8.84 -7.13 -8.36 -8.06 (3R)-3,7-Dimethylocta-1,6-dien-3-yl acetate -2.49 -3.57 -2.39 -2.12 -2.76 2-ethoxyethyl acetate -5.31 -4.85 -5.04 -4.48 -6.75 1,4-diamino-9,10-anthracenedione -11.85 -10.22 -8.10 -9.84 -9.21 1-amino-9,10-anthracenedione -9.44 -8.58 -7.93 -8.59 -8.51 2-amino-9,10-anthraquinone -11.53 -10.59 -7.98 -8.83 -10.81 1-(2-hydroxyethylamino)-9,10-anthraquinone -14.21 -12.14 -10.57 -13.77 -14.37 1-amino-4-hydroxy-9,10-anthracenedione -9.53 -9.37 -8.21 -11.08 -10.23 (2R,5R)-2-methyl-5-(1-methylethenyl)-cyclohexanone -3.75 -3.55 -3.32 -3.54 -3.95 6-isopropyl-3-methyl-1-cyclohex-2-enone -4.51 -3.61 -3.46 -3.17 -4.41 Amitriptyline -7.43 -6.14 -4.97 -6.58 -5.79 [2-benzhydryloxyethyl]-dimethyl-amine -9.34 -9.87 -8.04 -8.99 -7.91 (1S,5R)-2-methyl-5-(1-methylethenyl)-2-cyclohexen-1-ol -4.44 -3.84 -5.42 -4.86 -4.01 (2E)-3,7-dimethylocta-2,6-dien-1-ol -4.45 -4.56 -6.22 -5.24 -3.88 (2Z)-3,7-dimethylocta-2,6-dien-1-ol -4.78 -3.29 -5.82 -5.11 -3.57 1-butoxy-2-propanol -5.73 -4.89 -5.48 -5.46 -5.01 3,4-dichlorophenol -7.29 -5.78 -5.26 -6.89 -7.06 2-methoxyphenol -5.94 -5.88 -5.32 -3.39 -4.41 4-methyl-2-methoxyphenol -5.80 -8.26 -6.00 -5.59 -6.75 4-propylguaiacol -5.26 -7.36 -5.69 -4.02 -4.68 2,6-dimethoxyphenol -6.96 -8.79 -6.43 -7.38 -7.16 3,5-dichloro-2,6-dimethoxyphenol -6.44 -6.65 -5.07 -6.24 -5.86 1-benzylimidazole -7.63 -9.66 -10.07 -7.87 -9.60 RMSE 1.12 1.41 1.10 1.07 ME 0.06 0.31 0.33 0.10 31

exp pred Table S19: The experimental and predicted solvation free energy for the SAMPL 4 test set. ∆G is the experimental solvation free energy, ∆GAM1−BCC, pred pred pred ∆GMulliken, ∆GGasteiger, and ∆GSIESTA are the predicted solvation free energy with four different types of charges. The Amber mbondi2 force ﬁeld are employed for the atomic radius parametrization. The energy data are all in the unit of kcal/mol. exp pred pred pred pred Solute Name ∆G ∆GAM1−BCC ∆GMulliken ∆GGasteiger ∆GSIESTA cyclohexene 0.14 0.99 0.78 1.15 1.27 1,1-diphenylethene -2.78 -2.83 -2.39 -1.97 -1.58 2-methylbenzaldehyde -3.93 -2.92 -4.48 -3.35 -3.47 hexyl acetate -2.26 -2.45 -2.58 -2.44 -2.22 (2S,5R)-2-isopropyl-5-methylcyclohexanone -2.53 -2.95 -3.02 -3.23 -2.92 piperidine -5.11 -3.80 -3.82 -3.77 -3.40 (1R,2S,5R)-2-isopropyl-5-methylcyclohexanol -3.20 -3.59 -3.89 -4.15 -4.44 (2R,3R,4R,5R)-Hexan-1,2,3,4,5,6-hexol -23.62 -25.61 -22.47 -20.52 -24.15 2-ethylphenol -5.66 -5.61 -5.71 -5.75 -5.54 tetrahydropyran -3.12 -2.25 -2.10 -2.29 -1.78 1,4-dioxane -5.06 -5.12 -4.62 -4.86 -4.97 diphenyl ether -2.87 -1.72 -2.40 -1.52 -2.39 1,2-dimethoxybenzene -5.33 -4.89 -4.57 -6.68 -3.70 dibenzo-p-dioxin -3.15 -2.88 -3.68 -2.49 -4.26 anthracene -3.95 -4.11 -3.67 -3.96 -4.42 1-ethyl-2-methylbenzene -0.85 -0.69 -0.92 -0.88 -0.75 9,10-dihydroanthracene -3.78 -3.20 -3.58 -3.01 -4.63 HEXYL NITRATE -1.66 -1.08 -1.33 -1.65 -1.60 3-nitrooxypropyl nitrate -4.80 -5.73 -5.69 -5.85 -6.77 1,3-bis-(nitrooxy)butane -4.29 -4.83 -5.09 -4.80 -4.47 4-(1-Methylethenyl)-1-cyclohexene-1-carboxaldehyde -4.09 -3.56 -3.12 -2.77 -3.67 2-hydroxybenzaldehyde -4.68 -6.76 -6.39 -3.94 -7.05 2-chlorosyringaldehyde -7.78 -7.59 -6.71 -8.87 -7.07 2,6-dichlorosyringaldehyde -8.68 -6.47 -8.81 -9.60 -6.74 2-(2,3-dimethylphenyl)aminobenzoic acid -6.78 -8.61 -7.31 -8.45 -7.86 (3R)-3,7-Dimethylocta-1,6-dien-3-yl acetate -2.49 -2.85 -2.39 -2.12 -2.47 2-ethoxyethyl acetate -5.31 -4.85 -4.79 -5.08 -5.68 1,4-diamino-9,10-anthracenedione -11.85 -10.31 -7.62 -10.68 -9.37 1-amino-9,10-anthracenedione -9.44 -8.35 -7.43 -9.59 -9.49 2-amino-9,10-anthraquinone -11.53 -10.31 -8.33 -9.87 -11.41 1-(2-hydroxyethylamino)-9,10-anthraquinone -14.21 -12.40 -14.76 -13.67 -14.13 1-amino-4-hydroxy-9,10-anthracenedione -9.53 -8.93 -7.95 -10.89 -9.57 (2R,5R)-2-methyl-5-(1-methylethenyl)-cyclohexanone -3.75 -3.55 -3.32 -3.54 -3.95 6-isopropyl-3-methyl-1-cyclohex-2-enone -4.51 -3.61 -3.46 -3.17 -4.41 Amitriptyline -7.43 -6.34 -5.23 -6.82 -6.10 [2-benzhydryloxyethyl]-dimethyl-amine -9.34 -9.87 -8.34 -10.62 -8.53 (1S,5R)-2-methyl-5-(1-methylethenyl)-2-cyclohexen-1-ol -4.44 -3.84 -5.42 -5.65 -5.45 (2E)-3,7-dimethylocta-2,6-dien-1-ol -4.45 -4.46 -6.22 -6.20 -5.64 (2Z)-3,7-dimethylocta-2,6-dien-1-ol -4.78 -3.29 -5.82 -5.95 -5.06 1-butoxy-2-propanol -5.73 -4.89 -5.48 -5.46 -5.01 3,4-dichlorophenol -7.29 -5.78 -5.26 -6.89 -7.70 2-methoxyphenol -5.94 -5.25 -6.92 -5.67 -5.39 4-methyl-2-methoxyphenol -5.80 -7.64 -7.71 -8.05 -7.80 4-propylguaiacol -5.26 -6.95 -7.46 -6.61 -5.77 2,6-dimethoxyphenol -6.96 -8.40 -8.64 -9.07 -7.80 3,5-dichloro-2,6-dimethoxyphenol -6.44 -6.59 -6.95 -7.83 -5.89 1-benzylimidazole -7.63 -9.76 -10.16 -7.87 -9.76 RMSE 1.09 1.33 1.13 1.04 ME 0.15 0.14 -0.08 0.00 32

exp pred Table S20: The experimental and predicted solvation free energy for the SAMPL 4 test set. ∆G is the experimental solvation free energy, ∆GAM1−BCC, pred pred pred ∆GMulliken, ∆GGasteiger, and ∆GSIESTA are the predicted solvation free energy with four different types of charges. The ZAP9 force ﬁeld are employed for the atomic radius parametrization. The energy data are all in the unit of kcal/mol. exp pred pred pred pred Solute Name ∆G ∆GAM1−BCC ∆GMulliken ∆GGasteiger ∆GSIESTA cyclohexene 0.14 1.02 0.81 1.03 1.10 1,1-diphenylethene -2.78 -2.84 -2.43 -1.95 -1.57 2-methylbenzaldehyde -3.93 -3.48 -4.55 -3.41 -4.48 hexyl acetate -2.26 -2.50 -2.62 -2.41 -2.57 (2S,5R)-2-isopropyl-5-methylcyclohexanone -2.53 -3.07 -3.13 -3.17 -2.09 piperidine -5.11 -3.84 -3.85 -3.90 -3.04 (1R,2S,5R)-2-isopropyl-5-methylcyclohexanol -3.20 -3.81 -4.28 -4.12 -3.65 (2R,3R,4R,5R)-Hexan-1,2,3,4,5,6-hexol -23.62 -25.65 -24.63 -21.97 -23.66 2-ethylphenol -5.66 -5.75 -5.75 -6.00 -5.62 tetrahydropyran -3.12 -2.29 -2.21 -2.22 -1.94 1,4-dioxane -5.06 -4.98 -4.74 -4.62 -5.38 diphenyl ether -2.87 -2.11 -2.46 -1.67 -1.28 1,2-dimethoxybenzene -5.33 -5.18 -4.85 -6.19 -4.01 dibenzo-p-dioxin -3.15 -2.32 -4.31 -3.43 -4.23 anthracene -3.95 -4.30 -3.93 -3.92 -2.92 1-ethyl-2-methylbenzene -0.85 -0.59 -0.79 -0.90 -0.93 9,10-dihydroanthracene -3.78 -3.14 -3.50 -3.08 -3.34 HEXYL NITRATE -1.66 -1.19 -1.46 -1.71 -1.36 3-nitrooxypropyl nitrate -4.80 -5.73 -5.66 -5.87 -5.80 1,3-bis-(nitrooxy)butane -4.29 -4.85 -5.09 -4.80 -4.93 4-(1-Methylethenyl)-1-cyclohexene-1-carboxaldehyde -4.09 -3.19 -3.30 -2.72 -3.55 2-hydroxybenzaldehyde -4.68 -6.94 -7.61 -5.81 -6.48 2-chlorosyringaldehyde -7.78 -7.48 -8.69 -9.75 -6.86 2,6-dichlorosyringaldehyde -8.68 -6.87 -8.01 -10.52 -7.11 2-(2,3-dimethylphenyl)aminobenzoic acid -6.78 -8.30 -6.74 -7.89 -7.26 (3R)-3,7-Dimethylocta-1,6-dien-3-yl acetate -2.49 -2.71 -1.95 -1.74 -1.82 2-ethoxyethyl acetate -5.31 -5.60 -5.04 -4.70 -5.44 1,4-diamino-9,10-anthracenedione -11.85 -11.36 -9.37 -9.65 -9.04 1-amino-9,10-anthracenedione -9.44 -9.15 -8.76 -8.61 -7.32 2-amino-9,10-anthraquinone -11.53 -11.16 -9.63 -9.46 -9.46 1-(2-hydroxyethylamino)-9,10-anthraquinone -14.21 -11.63 -13.43 -14.23 -11.37 1-amino-4-hydroxy-9,10-anthracenedione -9.53 -9.81 -10.51 -10.54 -8.54 (2R,5R)-2-methyl-5-(1-methylethenyl)-cyclohexanone -3.75 -3.24 -3.40 -3.37 -3.06 6-isopropyl-3-methyl-1-cyclohex-2-enone -4.51 -3.34 -3.57 -3.07 -2.83 Amitriptyline -7.43 -5.99 -4.53 -6.66 -8.84 [2-benzhydryloxyethyl]-dimethyl-amine -9.34 -9.47 -7.45 -9.96 -9.80 (1S,5R)-2-methyl-5-(1-methylethenyl)-2-cyclohexen-1-ol -4.44 -4.60 -5.49 -5.43 -4.51 (2E)-3,7-dimethylocta-2,6-dien-1-ol -4.45 -5.36 -6.10 -6.01 -6.32 (2Z)-3,7-dimethylocta-2,6-dien-1-ol -4.78 -3.64 -5.90 -6.05 -5.70 1-butoxy-2-propanol -5.73 -4.98 -6.21 -5.52 -4.81 3,4-dichlorophenol -7.29 -5.82 -5.61 -6.14 -4.50 2-methoxyphenol -5.94 -5.92 -5.69 -5.67 -6.36 4-methyl-2-methoxyphenol -5.80 -8.41 -6.49 -7.69 -6.70 4-propylguaiacol -5.26 -7.47 -6.12 -6.62 -6.65 2,6-dimethoxyphenol -6.96 -8.73 -7.06 -8.70 -8.91 3,5-dichloro-2,6-dimethoxyphenol -6.44 -6.59 -5.80 -7.67 -4.33 1-benzylimidazole -7.63 -9.59 -9.77 -7.11 -9.08 RMSE 1.12 1.12 1.09 1.32 ME -0.01 0.07 -0.04 0.36