pka prediction on the sampl6 dataset — lessons learned —€¦ · · 2018-02-24— pka...

D3R/SAMPL Workshop, San Diego, 22-23 February 2018

pKa prediction on the SAMPL6 dataset

— Lessons learned —

Bogdan I. Iorga, Edithe SelwaInstitut de Chimie des Substances Naturelles, CNRS

Gif-sur-Yvette, France

Oliver Beckstein, Ian KenneyArizona State University

Phoenix, AZ


SAMPL6 pKa challenge dataset and requirements

2

Microstates provided: different protonation states and tautomers for 24 compounds (SMILES)

Requirements: Prediction Type I - microscopic pKasPrediction Type II - microstate populations as a function of pHPrediction Type III - macroscopic pKas


Choice of the method (I):Constant pH molecular dynamics (CpHMD)

3

Our previous participations to SAMPL challenges [1-3]: free energy calculations using MD simulations, with MDPOW (https://github.com/Becksteinlab/MDPOW) and OPLS-AA force field

At first sight, CpHMD looks very interesting

provides easily populations for microstates

implemented and thoroughly tested in AMBER for protein residues

CpHMD-related parametrization of all microstates in GAFF/AMBER: huge endeavor and missing expertise in our team

need for a reference compound with known experimental pKa value: blocking

1. Beckstein, O.; Iorga, B.I. JCAMD 2012, 26, 635-645.2. Beckstein, O.; Fourrier, A.; Iorga, B.I. JCAMD 2014, 28, 265-276.3. Kenney, I.M.; Beckstein, O.; Iorga, B.I. JCAMD 2016, 30, 1045-1058.

https://github.com/Becksteinlab/MDPOW


Choice of the method (II):Free energy calculations using non-equilibrium (fast-growth)

4

Protocol developed in our group based on PMX [4] and used in our participation to D3R GC2 [5] and GC3 for computing relative protein-ligand affinities

Possibility of computing relative free energies for transformations involving a change in the overall charge of the molecule

4. Gapsys, V.; Michielssens, S.; Seeliger, D.; de Groot, B.L. J. Comput. Chem. 2015, 36, 348-354.5. Selwa, E.; Elisée, E.; Zavala, A.; Iorga, B.I. JCAMD 2018, 32, 273-286.

A+→BP B+→A

30 Å


Free energy calculations using fast-growth molecular dynamics— pKa prediction —

5

M3+→M1M1→M2+

30 Å

RH+→RM1→M2+

30 Å

relative pKa values for all microstates – coupling with a SINGLE reference compound with known experimental value provides absolute pKa values for all microstates – general method

M1

M2+

M3+

M4++RH+

R


Free energy calculations using fast-growth molecular dynamics— pKa prediction —

6

absolute pKa values for all microstates – coupling every microstate with a reference compound with known experimental value – simple systems – probably better in terms of error propagation, but depending more on the accuracy of pKa experimental values

M1

M2+

M3+

M4++R1H+

R1

R4

R2

R3

R2H+

R4H+

R3H+

M3+→M1M1→M2+

30 Å

RH+→RM1→M2+

30 Å


Protocol for non-equilibrium (fast-growth) simulations

7

ligand common

core

ligand common

core

ligand common

core

A

B

A

B

Step 1: Generation of hybrid topology

Step 2: Conformational sampling using equilibrium MD

Ligand Atopology

Ligand Btopology

Hybridtopology

ligand common

coreB

A

Ligand A (λ = 0)MD 10 ns

Step 3: Structure morphing using non-equilibrium MD

frame A1 frame A100...

frame B1 frame B100...

λ = 0

Morphing A➞BMD 50 ps (λ0➞1)

λ = 1

frame B101 frame B200...

frame A101 frame A200...

λ = 1

Morphing B➞AMD 50 ps (λ1➞0)

λ = 0

Step 4: Free energy estimation

Analysis of trajectoriesCrooks-Gaussian Intersection

Bennett Acceptance RatioJarzynski estimator

ligand common

core

A

BLigand B (λ = 1)

MD 10 ns

Force field: mainly OPLS-AA and GAFF/AMBER

Ligand parametrization: MOL2FF (OPLS-AA) and AmberTools (GAFF/AMBER)

Generation of hybrid topologies: in house scripts

MD simulations: Gromacs

Analysis: PMX [4]4. Gapsys, V.; Michielssens, S.; Seeliger, D.; de Groot, B.L. J. Comput. Chem. 2015, 36, 348-354.

Selwa, E.; Elisée, E.; Zavala, A.; Iorga, B.I. JCAMD 2018, 32, 273-286.

Domański, J.; Beckstein, O.; Iorga, B. I., Ligandbook – an online repository for small and drug-like molecule force field parameters. Bioinformatics 2017, 33, 1747-1749 (https://ligandbook.org).

D3R/SAMPL Workshop, San Diego, 22-23 February 2018 8

AH+→AA→AH+

30 Å

Transformation Force field ΔΔG (kJ/mol)

phenolate/phenol OPLS-AA –4.65 ± 1.46

benzimidazolium/benzimidazole OPLS-AA 0.61 ± 0.48

SM15_micro001/SM15_micro004 OPLS-AA –3.56 ± 0.45

SM15_micro003/SM15_micro002 OPLS-AA 32.77 ± 0.43




SM22_micro002/SM22_micro003 OPLS-AA –2.63 ± 1.20


Free energy calculations using fast-growth molecular dynamics— intrinsic pKa prediction error —

RH+→RR→RH+

30 Å


RH+→RA→AH+

30 Å

Transformation Reference Force field ΔΔG (kJ/mol)

SM15_micro002/SM15_micro004 phenolate/phenol GAFF/AMBER 227.06 ± 0.51



SM22_micro002/SM22_micro001 pyridine/pyridinium GAFF/AMBER 442.05 ± 0.39


SM22_micro003/SM22_micro004 pyridine/pyridinium GAFF/AMBER 623.25 ± 0.39

Free energy calculations using fast-growth molecular dynamics— microscopic pKa prediction —

Predictions not submitted.


RH+→RA→AH+

30 Å

Transformation Reference Force field ΔΔG (kJ/mol)

SM15_micro002/SM15_micro004 phenolate/phenol OPLS-AA –8.45 ± 2.15

SM15_micro003/SM15_micro001 phenolate/phenol OPLS-AA –10.03 ± 2.26

SM15_micro001/SM15_micro004 benzimidazolium/benzimidazole OPLS-AA 100.81 ± 0.40

SM15_micro003/SM15_micro002 benzimidazolium/benzimidazole OPLS-AA 116.08 ± 0.42

SM20_micro003/SM20_micro004 phthalimidate/phthalimide OPLS-AA 911.67 ± 1.28

SM22_micro001/SM22_micro004 phenolate/phenol OPLS-AA 204.15 ± 2.18

SM22_micro002/SM22_micro001 pyridine/pyridinium OPLS-AA 227.31 ± 0.47

SM22_micro002/SM22_micro003 phenolate/phenol OPLS-AA 141.45 ± 1.36

SM22_micro003/SM22_micro004 pyridine/pyridinium OPLS-AA 289.16 ± 0.83

Free energy calculations using fast-growth molecular dynamics— microscopic pKa prediction —

Predictions not submitted.


Choice of the method (III):DFT calculations with correction for systematic errors

11

6. Muckerman, J.T.,;Skone, J.H.; Ning, M.; Wasada-Tsutsui, Y. Biochim. Biophys. Acta 2013, 1827, 882-891.

ΔGcorr = RTln(10) [ pKa(exp) – pKa(calc)]

geometry optimization B3LYP/6-311+G(d,p) 5d : E(g)

vibrational frequency calculation B3LYP/6-311+G(d,p) 5d: G0(g)

single-point energy calculation CPCM: E(g) + ΔG0solv

G*(H+(s)): –272.2 kcal/mol (literature value)

Protocol described in [6] using Gaussian09:

Values computed for a reference dataset (38 simple inorganic and organic compounds with known experimental pKa values) and for all microstates.

Computing time: between <1 min and 7 hours on a 8-core machine

For reference compounds:


Reference dataset

12

Acid (neutral) Base (negative) pKa Acid (positive) Base (neutral) pKa

nitric acid nitrate -1.40 anilinium aniline 4.62methanol methanolate 15.54 4-nitro anilinium 4-nitro aniline 0.98trifluoroethanol trifluoroethanolate 12.43 4-bromo anilinium 4-bromo aniline 3.89hexafluoroisopropanol hexafluoroisopropanolate 9.30 4-methoxy anilinium 4-methoxy aniline 5.36nonafluorotertbutanol nonafluorotertbutanolate 5.40 2,5-dichloro anilinium 2,5-dichloro aniline 1.53acetic acid acetate 4.76 pyridinium pyridine 5.24nitro acetic acid nitro acetate 1.68 3-nitro pyridinium 3-nitro pyridine 0.81phthalimide phthalimidine 8.30 2-chloro pyridinium 2-chloro pyridine 0.49uracil uracil anion 9.50 4-cyano pyridinium 4-cyano pyridine 1.86

sulfuric acid hydrosulfate -3.00 2,4,6-collidinium 2,4,6-collidine 7.33

benzenesulfonic acid benzenesulfonate -2.80 2,6-dimethyl pyridinium 2,6-dimethyl pyridine 6.70

methanesulfonic acid methanesulfonate -1.90 4-dimethylamino pyridinium 4-dimethylamino pyridine 9.60

trifluoroacetic acid trifluoroacetate 0.23 benzylammonium benzylamine 9.30

formic acid formate 3.77 triethylammonium triethylamine 10.72

benzoic acid benzoate 4.21 pyrrolidinium pyrrolidine 11.27

ethanol ethanolate 15.90 guanidinium guanidine 13.60

isopropanol isopropanolate 17.10 hydrazinium hydrazine 8.12

oxalic acid oxalate 1.38

phosphoric acid dihydrophosphate 2.15

phenol phenolate 9.95

4-nitro phenol 4-nitro phenolate 7.14


Reference dataset: global linear regression— correction for a systematic error —

13

y=3.7368x+2.7506R²=0.97388

-20

-10

0

10

20

30

40

50

60

70

80

-5.00 0.00 5.00 10.00 15.00 20.00

pKa (exp)

ΔGco

rr (

kcal

/mol

)

y = 3.7368x + 2.7506 R² = 0.97388


Reference dataset: linear regression for two separate datasets— correction for a systematic error —

14

y=3.7296x+1.3025R²=0.98273

-20

-10

0

10

20

30

40

50

60

70

80

-5.00 0.00 5.00 10.00 15.00 20.00

y=3.7262x+4.6539R²=0.97468

0

10

20

30

40

50

60

0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00

ΔGco

rr (

kcal

/mol

)

ΔGco

rr (

kcal

/mol

)

pKa (exp) pKa (exp)

Neutral acids Positively charged acids

y = 3.7368x + 2.7506 R² = 0.97388

y = 3.7296x + 1.3025 R² = 0.98273 y = 3.7262x + 4.6539 R² = 0.97468


pKa prediction for the SAMPL6 dataset

15

The same protocol applied to all microstates

Two types of corrections applied: either global or according to the charge of the acid form ⇒ two separate submissions

Global correction expected to be worse than separate corrections

Type I predictions submitted for all compounds

Type II and type III predictions submitted only for SM15, SM20 and SM22.

Compound pKa experimental pKa predicted (global correction)

pKa predicted (separate corrections)

SM15 4.70 ± 0.01 5.21 6.14

8.94 ± 0.01 11.41 10.64

SM20 5.70 ± 0.03 8.34 7.58

SM22 2.40 ± 0.02 1.31 2.02

7.43 ± 0.01 7.93 7.41

RMSE 1.72 (35bdm) 1.32 (p0jba)


Macroscopic pKa from microstates

16

• Input: relative free energies between micro states 1 ≤ k ≤ M

• Free energy of micro state k (relative to arbitrary reference state k=1):

• ΔGk can be computed from sums of ΔGmn that connect state 1 and state k.

• “Macroscopic” variable: number of protons N, with Nk the number of protons in state k.

• δNk,N is an “indicator” to pick out states with N protons

DGkl = Gk � Gl<latexit sha1_base64="T3Rk9goXE8WJrQiR5dkIp5ZnkKU=">AAACLHicbVBNSwMxEM3Wr1q/qp7ES7AIXixbEdSDUFTQYwVrC20ps2nahs0mS5IV6rL4a7zaX+NBxKv/QjDb9mBbBxIe783wZp4XcqaN6344mYXFpeWV7GpubX1jcyu/vfOoZaQIrRLJpap7oClnglYNM5zWQ0Uh8Ditef51qteeqNJMigczCGkrgJ5gXUbAWKqd32veUG4A37Zjnyf40gIfH9uft/MFt+iOCs+D0gQU0KQq7fxPsyNJFFBhCAetGyU3NK0YlGGE0yTXjDQNgfjQow0LBQRUt+LRCQk+tEwHd6WyTxg8Yv9OxBBoPQg82xmA6etZLSX/0xqR6Z63YibCyFBBxkbdiGMjcZoH7jBFieEDC4AoZnfFpA8KiLGpTbmEwG1oQk5dEqeOITzLxOZVmk1nHlRPihdF9/60UL6aBJdF++gAHaESOkNldIcqqIoIekGv6A0NnaHz7nw6X+PWjDOZ2UVT5Xz/AnxJqAI=</latexit><latexit sha1_base64="T3Rk9goXE8WJrQiR5dkIp5ZnkKU=">AAACLHicbVBNSwMxEM3Wr1q/qp7ES7AIXixbEdSDUFTQYwVrC20ps2nahs0mS5IV6rL4a7zaX+NBxKv/QjDb9mBbBxIe783wZp4XcqaN6344mYXFpeWV7GpubX1jcyu/vfOoZaQIrRLJpap7oClnglYNM5zWQ0Uh8Ditef51qteeqNJMigczCGkrgJ5gXUbAWKqd32veUG4A37Zjnyf40gIfH9uft/MFt+iOCs+D0gQU0KQq7fxPsyNJFFBhCAetGyU3NK0YlGGE0yTXjDQNgfjQow0LBQRUt+LRCQk+tEwHd6WyTxg8Yv9OxBBoPQg82xmA6etZLSX/0xqR6Z63YibCyFBBxkbdiGMjcZoH7jBFieEDC4AoZnfFpA8KiLGpTbmEwG1oQk5dEqeOITzLxOZVmk1nHlRPihdF9/60UL6aBJdF++gAHaESOkNldIcqqIoIekGv6A0NnaHz7nw6X+PWjDOZ2UVT5Xz/AnxJqAI=</latexit><latexit sha1_base64="T3Rk9goXE8WJrQiR5dkIp5ZnkKU=">AAACLHicbVBNSwMxEM3Wr1q/qp7ES7AIXixbEdSDUFTQYwVrC20ps2nahs0mS5IV6rL4a7zaX+NBxKv/QjDb9mBbBxIe783wZp4XcqaN6344mYXFpeWV7GpubX1jcyu/vfOoZaQIrRLJpap7oClnglYNM5zWQ0Uh8Ditef51qteeqNJMigczCGkrgJ5gXUbAWKqd32veUG4A37Zjnyf40gIfH9uft/MFt+iOCs+D0gQU0KQq7fxPsyNJFFBhCAetGyU3NK0YlGGE0yTXjDQNgfjQow0LBQRUt+LRCQk+tEwHd6WyTxg8Yv9OxBBoPQg82xmA6etZLSX/0xqR6Z63YibCyFBBxkbdiGMjcZoH7jBFieEDC4AoZnfFpA8KiLGpTbmEwG1oQk5dEqeOITzLxOZVmk1nHlRPihdF9/60UL6aBJdF++gAHaESOkNldIcqqIoIekGv6A0NnaHz7nw6X+PWjDOZ2UVT5Xz/AnxJqAI=</latexit>

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Note: we discuss free energies, but we can easily convert

DGk = Gk � G1<latexit sha1_base64="g1/1kbx83MInr6s+63nyukBTZnk=">AAACKXicbVBNSwMxEM3Wr1q/qoIXL8EieLHsiqAehKKCHiu4ttCWMpumbWg2WZKsUNf+Ga/213hSr/4OwXTbg219kOHxZoY3eUHEmTau++lkFhaXlleyq7m19Y3Nrfz2zqOWsSLUJ5JLVQ1AU84E9Q0znFYjRSEMOK0EvetRv/JElWZSPJh+RBshdARrMwLGSs38Xv2GcgP4ttnDl2k9ttVr5gtu0U2B54k3IQU0QbmZ/6m3JIlDKgzhoHXNcyPTSEAZRjgd5OqxphGQHnRozVIBIdWNJL1/gA+t0sJtqewTBqfq340EQq37YWAnQzBdPdsbif/1arFpnzcSJqLYUEHGRu2YYyPxKAzcYooSw/uWAFHM3opJFxQQYyObcomA28SEnPpJMnKM4FkObF7ebDrzxD8pXhTd+9NC6WoSXBbtowN0hDx0hkroDpWRjwh6Qa/oDQ2dofPufDhf49GMM9nZRVNwvn8BNnimRQ==</latexit><latexit sha1_base64="g1/1kbx83MInr6s+63nyukBTZnk=">AAACKXicbVBNSwMxEM3Wr1q/qoIXL8EieLHsiqAehKKCHiu4ttCWMpumbWg2WZKsUNf+Ga/213hSr/4OwXTbg219kOHxZoY3eUHEmTau++lkFhaXlleyq7m19Y3Nrfz2zqOWsSLUJ5JLVQ1AU84E9Q0znFYjRSEMOK0EvetRv/JElWZSPJh+RBshdARrMwLGSs38Xv2GcgP4ttnDl2k9ttVr5gtu0U2B54k3IQU0QbmZ/6m3JIlDKgzhoHXNcyPTSEAZRjgd5OqxphGQHnRozVIBIdWNJL1/gA+t0sJtqewTBqfq340EQq37YWAnQzBdPdsbif/1arFpnzcSJqLYUEHGRu2YYyPxKAzcYooSw/uWAFHM3opJFxQQYyObcomA28SEnPpJMnKM4FkObF7ebDrzxD8pXhTd+9NC6WoSXBbtowN0hDx0hkroDpWRjwh6Qa/oDQ2dofPufDhf49GMM9nZRVNwvn8BNnimRQ==</latexit><latexit sha1_base64="g1/1kbx83MInr6s+63nyukBTZnk=">AAACKXicbVBNSwMxEM3Wr1q/qoIXL8EieLHsiqAehKKCHiu4ttCWMpumbWg2WZKsUNf+Ga/213hSr/4OwXTbg219kOHxZoY3eUHEmTau++lkFhaXlleyq7m19Y3Nrfz2zqOWsSLUJ5JLVQ1AU84E9Q0znFYjRSEMOK0EvetRv/JElWZSPJh+RBshdARrMwLGSs38Xv2GcgP4ttnDl2k9ttVr5gtu0U2B54k3IQU0QbmZ/6m3JIlDKgzhoHXNcyPTSEAZRjgd5OqxphGQHnRozVIBIdWNJL1/gA+t0sJtqewTBqfq340EQq37YWAnQzBdPdsbif/1arFpnzcSJqLYUEHGRu2YYyPxKAzcYooSw/uWAFHM3opJFxQQYyObcomA28SEnPpJMnKM4FkObF7ebDrzxD8pXhTd+9NC6WoSXBbtowN0hDx0hkroDpWRjwh6Qa/oDQ2dofPufDhf49GMM9nZRVNwvn8BNnimRQ==</latexit>

b =1

kT<latexit sha1_base64="nLZ4vhFGK2K1ATOELRo7z5vUWZY=">AAACJ3icbZDLagIxFIYz9mbtzV523YRKoSuZkULbRUHopksLThVU5EzMaDCTDEmmoIPv0m19mq5Ku+yDFJpRF1V7IPDzn3P4T74g5kwb1/1ychubW9s7+d3C3v7B4VHx+ORZy0QR6hPJpWoGoClngvqGGU6bsaIQBZw2guFD1m+8UKWZFHUzimkngr5gISNgrNUtnrUDagDf43aogKTeJB3WJ91iyS27s8LrwluIElpUrVv8afckSSIqDOGgdctzY9NJQRlGOJ0U2ommMZAh9GnLSgER1Z10dv0EX1qnh0Op7BMGz9y/GylEWo+iwE5GYAZ6tZeZ//VaiQlvOykTcWKoIPOgMOHYSJyhwD2mKDF8ZAUQxeytmAzAYjAW2FJKDNzyEnLpJ2mWGMNYZry8VTrrwq+U78ru03WpWlmAy6NzdIGukIduUBU9ohryEUFj9Ire0NSZOu/Oh/M5H805i51TtFTO9y+Va6cl</latexit><latexit sha1_base64="nLZ4vhFGK2K1ATOELRo7z5vUWZY=">AAACJ3icbZDLagIxFIYz9mbtzV523YRKoSuZkULbRUHopksLThVU5EzMaDCTDEmmoIPv0m19mq5Ku+yDFJpRF1V7IPDzn3P4T74g5kwb1/1ychubW9s7+d3C3v7B4VHx+ORZy0QR6hPJpWoGoClngvqGGU6bsaIQBZw2guFD1m+8UKWZFHUzimkngr5gISNgrNUtnrUDagDf43aogKTeJB3WJ91iyS27s8LrwluIElpUrVv8afckSSIqDOGgdctzY9NJQRlGOJ0U2ommMZAh9GnLSgER1Z10dv0EX1qnh0Op7BMGz9y/GylEWo+iwE5GYAZ6tZeZ//VaiQlvOykTcWKoIPOgMOHYSJyhwD2mKDF8ZAUQxeytmAzAYjAW2FJKDNzyEnLpJ2mWGMNYZry8VTrrwq+U78ru03WpWlmAy6NzdIGukIduUBU9ohryEUFj9Ire0NSZOu/Oh/M5H805i51TtFTO9y+Va6cl</latexit><latexit sha1_base64="nLZ4vhFGK2K1ATOELRo7z5vUWZY=">AAACJ3icbZDLagIxFIYz9mbtzV523YRKoSuZkULbRUHopksLThVU5EzMaDCTDEmmoIPv0m19mq5Ku+yDFJpRF1V7IPDzn3P4T74g5kwb1/1ychubW9s7+d3C3v7B4VHx+ORZy0QR6hPJpWoGoClngvqGGU6bsaIQBZw2guFD1m+8UKWZFHUzimkngr5gISNgrNUtnrUDagDf43aogKTeJB3WJ91iyS27s8LrwluIElpUrVv8afckSSIqDOGgdctzY9NJQRlGOJ0U2ommMZAh9GnLSgER1Z10dv0EX1qnh0Op7BMGz9y/GylEWo+iwE5GYAZ6tZeZ//VaiQlvOykTcWKoIPOgMOHYSJyhwD2mKDF8ZAUQxeytmAzAYjAW2FJKDNzyEnLpJ2mWGMNYZry8VTrrwq+U78ru03WpWlmAy6NzdIGukIduUBU9ohryEUFj9Ire0NSZOu/Oh/M5H805i51TtFTO9y+Va6cl</latexit>


Macroscopic pKa from microstates

17

• Free energy difference between two macro states N and N-1 (i.e., adding one proton)

bDGN,N�1

= � ln

2

6664

MÂ

k=1

exp(�bDGk)dNk ,N

MÂ

k=1

exp(�bDGk)dNk ,N�1

3

7775

<latexit sha1_base64="Hw7033wgmx2dUP13hTH/mRQisOE=">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</latexit><latexit sha1_base64="Hw7033wgmx2dUP13hTH/mRQisOE=">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</latexit><latexit sha1_base64="Hw7033wgmx2dUP13hTH/mRQisOE=">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</latexit>

• Free energy difference for protonation reaction (taking into account hydration free energy of the proton)

A� + H+ ⌦ HA<latexit sha1_base64="kuzjpBAFK7yrQVNsRSmDAJBeGhI=">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</latexit><latexit sha1_base64="kuzjpBAFK7yrQVNsRSmDAJBeGhI=">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</latexit><latexit sha1_base64="kuzjpBAFK7yrQVNsRSmDAJBeGhI=">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</latexit>

DG = DGN,N�1 � DGhyd(H+)

<latexit sha1_base64="wupF/AV2RXuv7hKDQO115yCgcpk=">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</latexit><latexit sha1_base64="wupF/AV2RXuv7hKDQO115yCgcpk=">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</latexit><latexit sha1_base64="wupF/AV2RXuv7hKDQO115yCgcpk=">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</latexit>

• Effective (or “macroscopic” pKa):

pKa = bDG/ ln 10<latexit sha1_base64="vvwOinOenFsYy1pOIMmaWin3VMg=">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</latexit><latexit sha1_base64="vvwOinOenFsYy1pOIMmaWin3VMg=">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</latexit><latexit sha1_base64="vvwOinOenFsYy1pOIMmaWin3VMg=">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</latexit>


Concluding remarks

18

Approaches involving QM and QSPR methods seem to be currently the best options for computing pKa values, in terms of speed and accuracy (method dependent).

MD simulations (free energy calculations) represent an interesting alternative, for the moment hampered by difficulties in parametrization of species involved, the computing time required and the quality of force field parameters.

In the tradition of SAMPL challenges, after hydration free energies and partition coefficients, pKas have a huge potential in the improvement of currently available force fields.


Acknowledgements

D3R/SAMPL organizers

ICSN, CNRS, Gif-sur-Yvette, FranceEdithe SELWA Agustin ZAVALAEddy ELISEELudovic CHAPUTHristo NEDEVPascal RETAILLEAU

Arizona State UniversityOliver BECKSTEIN Ian KENNEY

Max Planck Institute for Biophysical Chemistry, Göttingen, GermanyBert DE GROOT (PMX)

19

ANR-10-LABX-33

pka prediction on the sampl6 dataset — lessons learned —€¦ · · 2018-02-24— pka...

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