The Good, the Bad, and the Ugly: “HiPen”, a New Dataset for Validating (S)QM/MM Free Energy Simulations
Abstract
:1. Introduction
2. Results
3. Discussion
3.1. The Good
3.1.1. Molecule 2
3.1.2. Molecule 11
3.2. The Bad
3.2.1. Molecule 5
3.2.2. Molecule 6
3.3. The Ugly
3.3.1. Molecule 8
3.3.2. Molecule 9
4. Materials and Methods
4.1. Equilibrium Simulations
4.2. Nonequilibrium “Switching” Simulations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
MM | Molecular Mechanics |
QM | Quantum Mechanics |
SQM | Semiempirical Quantum Mechanics |
QM/MM | Quantum Mechanical/Molecular Mechanical hybrid methods |
SQM/MM | Semiempirical Quantum Mechanical/Molecular Mechanical hybrid methods |
FEP | Free Energy Perturbation |
BAR | Bennett’s Acceptance Ratio |
JAR | Jarzynski’s equation |
CRO | Crooks’ equation |
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Sample Availability: Samples of the compounds are not available from the authors. |
ZINC ID | CGenFF Penalties | Offset (kcal/mol) | |||
---|---|---|---|---|---|
Param | Charge | ||||
1 | 00061095 | 36/21 | 432.10 | 200.99 | 29,000 |
2 | 00077329 | 16/10 | 378.50 | 347.24 | 15,000 |
3 | 00079729 | 18/13 | 683.00 | 207.72 | 17,000 |
4 | 00086442 | 21/12 | 312.50 | 283.62 | 19,000 |
5 | 00087557 | 31/17 | 378.50 | 347.31 | 25,000 |
6 | 00095858 | 25/16 | 567.90 | 361.40 | 25,000 |
7 | 00107550 | 21/11 | 378.50 | 347.29 | 16,000 |
8 | 00107778 | 22/15 | 378.50 | 347.29 | 21,000 |
9 | 00123162 | 34/21 | 385.50 | 217.28 | 29,000 |
10 | 00133435 | 34/22 | 470.50 | 27.14 | 28,000 |
11 | 00138607 | 36/20 | 336.00 | 261.56 | 29,000 |
12 | 00140610 | 20/12 | 449.00 | 214.90 | 17,000 |
13 | 00164361 | 23/14 | 424.00 | 194.49 | 20,000 |
14 | 00167648 | 44/26 | 436.50 | 226.60 | 35,000 |
15 | 00169358 | 26/16 | 540.40 | 142.16 | 22,000 |
16 | 01755198 | 28/12 | 329.00 | 21.11 | 19,000 |
17 | 01867000 | 32/18 | 470.50 | 5.82 | 22,000 |
18 | 03127671 | 41/24 | 329.00 | 25.20 | 34,000 |
19 | 04344392 | 52/29 | 329.00 | 24.78 | 40,000 |
20 | 04363792 | 28/21 | 698.00 | 185.49 | 28,000 |
21 | 06568023 | 30/18 | 329.00 | 21.60 | 25,000 |
22 | 33381936 | 33/21 | 545.50 | 395.62 | 30,000 |
FEP (fw) | FEP (bw) | BAR | Overlap (%) | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Hyst | Hyst | Hyst | ||||||||||||||
1 | −301.11 | 4.08 | 5.29 | −282.47 | 7.89 | −3.14 | 305.82 | 1.87 | 2.02 | 322.87 | 7.30 | −3.29 | −303.34 | −0.15 | 3.15 | 0.04 |
2 | −255.52 | 0.19 | 0.51 | −245.10 | 4.29 | −1.15 | 258.88 | 0.29 | 0.60 | 268.72 | 5.28 | −1.47 | −256.87 | −0.05 | 0.11 | 0.28 |
3 | −412.88 | 0.35 | 0.65 | −402.47 | 3.49 | −1.17 | 416.38 | 0.54 | 0.78 | 428.26 | 4.86 | −2.06 | −414.19 | −0.01 | 0.01 | 0.12 |
4 | −254.51 | 0.43 | 0.69 | −239.09 | 5.66 | −2.43 | 259.24 | 0.51 | 0.84 | 269.67 | 4.34 | −1.64 | −256.34 | 0.00 | 0.03 | 0.06 |
5 | −589.94 | 2.30 | 2.38 | −570.06 | 5.78 | −3.41 | 604.61 | 2.25 | 2.49 | 626.49 | 7.84 | −4.29 | −596.97 | 0.48 | 0.25 | 0.00 |
6 | −109.58 | 2.58 | 2.59 | −86.31 | 7.14 | −4.07 | 130.57 | 4.83 | 4.41 | 162.27 | 10.42 | −6.04 | −118.33 | 0.56 | 2.35 | 0.00 |
7 | −992.13 | 0.33 | 0.67 | −982.02 | 3.94 | −1.06 | 994.96 | 4.83 | 12.05 | 1011.88 | 19.05 | −3.26 | −993.15 | 0.21 | 0.49 | 0.28 |
8 | −994.00 | 4.16 | 4.03 | −982.45 | 4.39 | −1.46 | 988.29 | 9.09 | 5.74 | 1009.22 | 7.77 | −4.10 | −992.02 | 1.03 | 14.08 | 3.72 |
9 | −447.42 | 2.99 | 3.12 | −423.12 | 9.04 | −4.27 | 451.15 | 8.94 | 4.93 | 475.54 | 6.40 | −4.77 | −449.44 | 1.02 | 5.61 | 0.02 |
10 | −336.30 | 0.84 | 0.99 | −320.41 | 5.46 | −2.54 | 341.91 | 0.31 | 0.72 | 352.24 | 4.10 | −1.61 | −337.98 | 0.11 | 0.07 | 0.04 |
11 | −460.25 | 1.37 | 1.30 | −441.09 | 7.09 | −3.26 | 464.90 | 1.43 | 1.15 | 482.37 | 8.89 | −3.38 | −461.88 | 0.11 | 0.07 | 0.02 |
12 | −70.74 | 2.17 | 1.31 | −54.33 | 4.82 | −2.66 | 84.97 | 0.85 | 1.21 | 115.59 | 11.07 | −5.86 | −77.20 | 0.25 | 0.02 | 0.00 |
13 | −556.49 | 2.79 | 1.67 | −547.25 | 5.39 | −3.27 | 571.83 | 1.37 | 1.32 | 587.80 | 5.62 | −3.28 | −567.59 | 0.18 | 0.15 | 0.01 |
14 | −80.28 | 0.79 | 0.97 | −65.97 | 4.62 | −2.17 | 85.55 | 0.78 | 0.77 | 100.32 | 6.15 | −2.89 | −82.62 | 0.12 | 0.10 | 0.03 |
15 | −406.76 | 0.18 | 0.46 | −398.31 | 3.39 | −0.56 | 408.29 | 0.32 | 0.54 | 419.87 | 5.52 | −2.04 | −407.59 | 0.02 | 0.00 | 0.51 |
16 | −633.17 | 1.32 | 1.57 | −621.65 | 4.28 | −1.45 | 638.22 | 2.26 | 2.73 | 664.09 | 8.08 | −5.12 | −636.14 | 0.72 | 0.68 | 0.05 |
17 | −673.11 | 0.21 | 0.55 | −664.21 | 3.29 | −0.70 | 672.67 | −0.13 | 0.71 | 682.01 | 3.11 | −1.71 | −673.41 | −0.03 | 0.01 | 0.69 |
18 | −518.20 | 1.82 | 1.80 | −501.32 | 5.34 | −2.76 | 525.15 | 4.99 | 4.91 | 551.31 | 9.84 | −5.09 | −520.79 | 0.90 | 3.94 | 0.10 |
19 | −879.27 | 3.54 | 2.13 | −857.72 | 6.10 | −3.74 | 892.96 | 1.86 | 2.43 | 918.55 | 9.50 | −4.99 | −885.39 | 0.51 | 0.21 | 0.00 |
20 | −691.39 | 3.08 | 4.83 | −676.22 | 6.43 | −2.37 | 713.26 | 0.83 | 1.34 | 753.13 | 14.99 | −7.29 | −702.33 | 0.83 | 1.13 | 0.00 |
21 | −70.62 | 2.52 | 1.58 | −59.20 | 3.66 | −1.43 | 69.86 | 1.10 | 1.30 | 87.37 | 8.66 | −3.39 | −69.33 | 0.25 | 0.84 | 0.37 |
22 | −177.51 | 0.73 | 0.97 | −165.15 | 4.25 | −1.68 | 181.81 | 0.82 | 1.04 | 213.38 | 37.01 | −6.02 | −179.19 | 0.14 | 0.22 | 0.07 |
JAR (fw) | JAR (bw) | CRO | Overlap (%) | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Hyst | Hyst | Hyst | W | |||||||||||||
1 | −305.97 | 2.92 | 3.87 | −299.85 | 5.07 | −0.80 | 300.95 | 0.47 | 0.39 | 302.15 | 1.97 | 1.60 | −301.61 | 0.53 | 4.44 | 32.71 |
2 | −272.53 | 0.21 | 0.48 | −271.48 | 0.60 | 1.86 | 271.88 | 0.13 | 0.48 | 272.59 | 1.59 | 2.19 | −271.84 | 0.09 | 0.08 | 53.89 |
3 | −408.69 | 0.00 | 0.03 | −408.18 | 0.90 | 2.40 | 408.63 | 0.00 | 0.05 | 409.03 | 0.63 | 2.57 | −408.66 | 0.00 | 0.00 | 56.68 |
4 | −271.25 | 0.00 | 0.03 | −271.10 | 0.41 | 3.02 | 271.15 | 0.00 | 0.02 | 271.31 | 0.49 | 3.00 | −271.20 | 0.00 | 0.00 | 79.52 |
5 | −539.16 | 0.58 | 0.98 | −535.17 | 1.98 | 0.08 | 537.50 | 2.26 | 2.71 | 543.25 | 3.18 | −0.66 | −538.78 | 0.36 | 0.37 | 8.76 |
6 | −143.51 | 3.69 | 2.10 | −137.78 | 2.08 | −0.65 | 138.57 | 1.46 | 2.12 | 143.83 | 3.12 | −0.47 | −140.17 | 0.41 | 1.70 | 23.95 |
7 | −999.40 | 0.42 | 0.69 | −998.41 | 0.69 | 1.91 | 998.80 | 1.37 | 2.82 | 1000.98 | 3.29 | 1.03 | −999.02 | 0.42 | 0.28 | 44.88 |
8 | −995.50 | 3.54 | 3.79 | −990.77 | 4.06 | −0.25 | 989.35 | 6.99 | 4.61 | 998.13 | 4.05 | −1.69 | −995.41 | 0.90 | 9.68 | 24.92 |
8 (5 ps) | −995.88 | 2.90 | 3.74 | −991.48 | 4.16 | −0.18 | 989.36 | 7.05 | 3.29 | 997.91 | 3.78 | −1.71 | −995.87 | 0.68 | 1.60 | 27.70 |
9 | −426.22 | 1.72 | 1.95 | −414.69 | 8.21 | −2.48 | 415.08 | 7.74 | 5.19 | 428.09 | 4.12 | −2.87 | −423.89 | 0.91 | 8.28 | 22.83 |
9 (5 ps) | −426.53 | −0.28 | 1.04 | −419.30 | 7.09 | −1.24 | 412.65 | 9.23 | 5.75 | 425.23 | 4.45 | −2.95 | −425.45 | 1.22 | 6.82 | 60.27 |
10 | −285.45 | 0.02 | 0.15 | −284.78 | 0.82 | 2.25 | 285.36 | 0.00 | 0.03 | 286.22 | 1.18 | 2.03 | −285.41 | 0.01 | 0.00 | 46.14 |
11 | −510.05 | 0.02 | 0.17 | −507.81 | 2.93 | 0.99 | 509.50 | 0.23 | 0.41 | 510.72 | 0.96 | 1.68 | −509.92 | 0.03 | 0.01 | 44.12 |
12 | −81.64 | 0.00 | 0.03 | −81.37 | 0.55 | 2.78 | 81.48 | 0.00 | 0.03 | 81.77 | 0.63 | 2.73 | −81.56 | 0.00 | 0.00 | 72.35 |
13 | −558.93 | 0.00 | 0.02 | −558.82 | 0.36 | 3.13 | 558.80 | 0.00 | 0.01 | 558.91 | 0.36 | 3.12 | −558.86 | 0.00 | 0.00 | 84.07 |
14 | −61.10 | 0.00 | 0.05 | −60.35 | 0.91 | 2.08 | 60.95 | −0.01 | 0.09 | 61.75 | 0.99 | 1.97 | −61.03 | 0.02 | 0.00 | 45.35 |
15 | −408.64 | 0.00 | 0.02 | −408.50 | 0.39 | 2.63 | 408.56 | 0.00 | 0.00 | 408.70 | 0.42 | 3.03 | −408.59 | 0.01 | 0.00 | 76.59 |
16 | −604.94 | 1.73 | 2.59 | −600.37 | 2.46 | −0.55 | 599.77 | 2.54 | 0.82 | 607.38 | 4.70 | −1.37 | −602.79 | 0.52 | 2.78 | 33.53 |
17 | −672.92 | 0.00 | 0.02 | −672.79 | 0.38 | 3.08 | 672.88 | 0.00 | 0.01 | 673.01 | 0.41 | 3.07 | −672.90 | 0.00 | 0.00 | 76.92 |
18 | −533.65 | 2.30 | 2.30 | −527.81 | 2.42 | −0.69 | 529.28 | 2.69 | 3.09 | 536.11 | 5.43 | −1.05 | −530.42 | 0.61 | 3.72 | 26.08 |
19 | −912.05 | 4.65 | 3.21 | −904.31 | 3.36 | −1.53 | 906.22 | 0.00 | 0.81 | 909.91 | 3.03 | 0.05 | −907.05 | 0.45 | 1.40 | 25.82 |
20 | −704.48 | 2.63 | 4.45 | −699.99 | 4.35 | −0.18 | 697.46 | 5.67 | 3.51 | 706.31 | 2.49 | −1.72 | −704.26 | 0.77 | 7.32 | 13.21 |
21 | −55.94 | 1.36 | 1.40 | −53.45 | 1.12 | 0.82 | 53.51 | −0.02 | 0.04 | 54.19 | 1.09 | 2.05 | −53.70 | 0.09 | 0.53 | 60.60 |
22 | −172.40 | 6.19 | 3.39 | −162.42 | 1.51 | −2.45 | 165.24 | 0.37 | 0.78 | 171.36 | 7.48 | −0.80 | −165.13 | 0.11 | 0.20 | 9.71 |
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Kearns, F.L.; Warrensford, L.; Boresch, S.; Woodcock, H.L. The Good, the Bad, and the Ugly: “HiPen”, a New Dataset for Validating (S)QM/MM Free Energy Simulations. Molecules 2019, 24, 681. https://doi.org/10.3390/molecules24040681
Kearns FL, Warrensford L, Boresch S, Woodcock HL. The Good, the Bad, and the Ugly: “HiPen”, a New Dataset for Validating (S)QM/MM Free Energy Simulations. Molecules. 2019; 24(4):681. https://doi.org/10.3390/molecules24040681
Chicago/Turabian StyleKearns, Fiona L., Luke Warrensford, Stefan Boresch, and H. Lee Woodcock. 2019. "The Good, the Bad, and the Ugly: “HiPen”, a New Dataset for Validating (S)QM/MM Free Energy Simulations" Molecules 24, no. 4: 681. https://doi.org/10.3390/molecules24040681