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. 2022 Jun 8;9:899805. doi: 10.3389/fmolb.2022.899805

TABLE 1.

Quantitative in silico calculations (we highlighted in boldface the simulations that are below one order of magnitude for the predicted results with respect to the experimental ones)

Target Technique T [K] Force field k off (sim) [s−1] k off (Exp) [s−1] Simulation time [µs] Ref Year
Trypsin/Benzamidine SEEKR 298 Amber14SB + GAFF 83 ± 14 600 ± 300 19 10.1021/acs.jpcb.6b09388 2017
Trypsin/Benzamidine SEEKR 298 Amber14SB + GAFF 174 ± 9 600 ± 300 4.4 10.1021/acs.jctc.0c00495 2020
Trypsin/Benzamidine SEEKR2 298 Amber14SB + GAFF 990 ± 70 600 ± 300 5 10.26434/chemrxiv-2021-pplfs 2021
Trypsin/Benzamidine M-WEM 298 Amber14SB + GAFF 791 ± 197 600 ± 300 0.48 10.1021/acs.jctc.1c00803 2022
Trypsin/Benzamidine Inf-MetaD 300 Amber99SB-ILDN  9.1 ± 2.5 600 ± 300 5 10.1073/pnas.1424461112 2015
Trypsin/Benzamidine Inf-MetaD 300 Amber14SB + GAFF 4176 ± 324 600 ± 300 — 10.1021/acs.jctc.8b00934 2019
Trypsin/Benzamidine MSM 298 Amber99SB + GAFF (9.5 ± 3.3)·104 600 ± 300 50 10.1073/pnas.1103547108 2011
Trypsin/Benzamidine MSM — — 2.8 ·104 600 ± 300 7.7 10.1021/ct400919u 2014
Trypsin/Benzamidine MSM — Amber99SB + GAFF 131 ± 109 600 ± 300 149.1 10.1038/ncomms8653 2015
Trypsin/Benzamidine MSM 298 Amber99SB + GAFF 1170 [617, 2120] 600 ± 300 58.28 10.1073/pnas.1525092113 2016
Trypsin/Benzamidine WExplore 300 Charmm36 + CGenFF 5.56 ·104 600 ± 300 4.1 10.1016/j.bpj.2017.01.006 2017
Trypsin/Benzamidine REVO 300 Charmm36 + CGenFF 2660 600 ± 300 8.75 10.1063/1.5100521 2019
Trypsin/Benzamidine LiGaMD 300 Amber14SB + GAFF 3.53 ± 1.41 600 ± 300 5 10.1021/acs.jctc.0c00395 2020
Trypsin/Benzamidine dcTMD 290 Amber99SB* 270 ± 40 600 ± 300 10000 c 10.1038/s41467-020-16655-1 2020
Trypsin/Benzamidine AMS 298 Charmm36 + CGenFF 260 ± 240 600 ± 300 2.3 10.1021/acs.jctc.6b00277 2016
Trypsin/Benzamidine OPES 300 Amber14SB + GAFF 687 600 ± 300 3.2 arXiv:2204.05572 2022
T4L L99A-Benzene In-MetaD 300 Charmm22* 6.0 ± 2.2 950 ± 200 a 6.7 10.1039/c7sc01627a 2017
T4L L99A-Benzene FA-MetaD 300 Charmm22* 5.7 ± 2.3 950 ± 200 a 5.5 10.1063/1.5024679 2018
T4L L99A-Benzene In-MetaD 303 Charmm36 270 ± 100 950 ± 200 — 10.1371/journal.pcbi.1006180 2018
T4L L99A-Benzene MSM 303 Charmm36 310 ± 130 950 ± 200 60 10.1371/journal.pcbi.1006180 2018
T4L L99A-Indole In-MetaD 300 Charmm22* + CGenFF 9.8 ± 10.2 325 ± 75 b 4.5 10.1063/1.5024679 2018
T4L L99A-Indole FA-MetaD 300 Charmm22* + CGenFF 6.0 ± 3.7 325 ± 75 b 2.0 10.1063/1.5024679 2018
µOpioid receptor-morphine In-MetaD 300 Charmm36 + CGenFF (5.7 ± 0.5)·10–2 (2.3 ± 0.2)·10–2 6 10.1063/5.0019100 2020
µOpioid receptor-bruprenorphine In-MetaD 300 Charmm36 + CGenFF (2.1 ± 0.3)·10–2 (1.8 ± 0.3)·10–3 19 10.1063/5.0019100 2020
µOpioid receptor-Fentanyl In-MetaD 310 Charmm36m + CGenFF (2.6 ± 0.8)·10–2 (HID) (3.8 ± 1.4)·10–1 (HIE) 1.1 ± 0.3 (HIP) 4.2 · 10–3 6 10.1021/jacsau.1c00341 2021
TSPO-PK11195 REVO 300 Charmm36 + CGenFF (D1)6.4 · 10–5 (D2)6.67·101 (D3)6.4 · 10–3 (D4)4.1 · 10–3 (4RYI)6.0 · 10–4 (D1-D4 different docked poses) 4.9 · 10–4 40 10.1016/j.bpj.2020.11.015 2021
c-Src kinase-dasatinib In-MetaD 300 OPLS (4.8 ± 2.4)·10–2 5.6 · 10–2 1.1 · 10–3 ∼7–8 10.1126/sciadv.1700014 2017
Src kinase - imatinib TS-PPTIS 305 Amber99SB*-ILDN + GAFF (QM/MM) 0.026 0.11 ± 0.08 — 10.1021/acs.jctc.8b00687 2018
Epoxide Hydrolase-TPPU WExplore 300 Charmm36 + CGenFF 2.4 · 10–2 [3.6 · 10–3 s−1, 4.4 · 10–2 s−1] 1.5 · 10–3 6 10.1021/jacs.7b08572 2018
p38 kinase/1-(3-(tert-butyl)-1- (p-tolyl)-1H-pyrazol-5-yl)urea In-MetaD 300 Amber99SB-ILDN + GAFF 0.020 ± 0.011 0.14 6.8 10.1021/jacs.6b12950 2017
M2 muscarinic receptor/iperoxo FA-MetaD 310 Amber14SB + GAFF (3.7 ± 0.7)·10–4 (1.0 ± 0.2)·10–2 8 10.1021/acs.jpclett.0c00999 2020
HSP90-inhibitor dcTMD 300 Amber99SB + GAFF (1.6 ± 0.2)·10–3 (3.4 ± 0.2)·10–2 5000 c 10.1038/s41467-020-16655-1 2020
Mdm2/PMI MSM 300 Amber99SB-ILDN 0.125 [0.025, 0.66] 1.13 [0.48, 1.33] (Different rate matrix estimators) 0.037 [0.029, 0.04] 500 10.1038/s41467-017-01163-6 2017
Mdm2/p53 MSM 300 Amber99SB-ILDN-NMR 1.9·105 2.1 831 10.1016/j.bpj.2017.07.009 2017
SH3 Domain—1CKB Pep-GaMD 300 Amber14SB (1.45 ± 1.17)·10–3 8.9 · 10–3 3 10.1063/5.0021399 2020
MtKatG—Isonazid τRAMD + extrapolation 300 CHARMM36 + SwissParam (2.8 ± 3.7)·10–2 (2.0 ± 0.3)·10–2 — 10.1021/acs.jpclett.1c02952 2021
a

The Authors in the original work considered the experimental koff at 293 K (800 ± 200 s−1), while they simulated the system at 300 K. Here we choose to put the value at the closest temperature available in experiments (303K—950 ± 200 s−1). Both the experimental values come from (Feher et al., 1996).

b

The experimental value has been measured at 293 K.

c

For dcTMD, computational time is referred to 1D Langevin simulator, and the authors says that “1 ms of simulation time at a 5 fs time step take ∼6 h of wall-clock time on a single CPU”.