This document discusses sources of error in predicting accurate absolute binding energies in aqueous solution using electronic structure methods. It identifies several potential sources of error, including imaginary frequencies, anharmonic effects, treatment of ions, explicit solvation modeling, conformational sampling, treatment of protonation states, and harmonic approximations. It recommends using methods like DFT-D3/QZVP, PM6-D3H, and COSMO-RS to calculate solvation energies and binding affinities while addressing these error sources.

1. Department
of
Chemistry
CC-­‐BY
1
Predic'ng
accurate
absolute
binding
energies
in
aqueous
solu'on:
thermodynamic
considera'ons
for
electronic
structure
methods
arXiv.org:
1501.04428
(submiBed
to
PCCP)
Jan
H.
Jensen
University
of
Copenhagen
twi9er:
@janhjensen
Google+:
+JanJensenCopenhagen
Youtube:
molmodbasics
Blog:
Molecular
Modeling
Basics
&
Proteins
and
Wave
FuncRons

2. Department
of
Chemistry
2
DFT-­‐D3/
QZVP
HF-­‐3c
(PM6-­‐D3H)
(DFTB2-­‐D3H)
COSMO-­‐RS
Grimme:
DOI
10.1021/jp411616b
Also:
DOI
10.1002/chem.201200497

3. Department
of
Chemistry
3
DFT-­‐D3/
QZVP
HF-­‐3c
(PM6-­‐D3H)
(DFTB2-­‐D3H)
COSMO-­‐RS
Grimme:
DOI
10.1021/jp411616b
Also:
10.1002/chem.201200497

4. Department
of
Chemistry
4
3-­‐body
dispersion
&
RRHO
crucial
DFT-­‐D3/
QZVP
PM6-­‐D3H
(DFTB2-­‐D3H)
COSMO-­‐RS
Grimme:
DOI
10.1002/chem.201200497
MAD:
2
kcal/mol

5. Department
of
Chemistry
5

6. Department
of
Chemistry
6
Possible
sources
of
error
Imaginary
frequencies
Anharmonic
effects
Ions
Explicit
solvaRon
ConformaRonal
sampling
Changing
protonaRon
state
Explicit
ions

7. Department
of
Chemistry
7
Conforma'onal
Sampling
Must
find
lowest
Go
conformaRon
(duh)
Must
find
all
low-­‐Go
conformaRons?
Nconf
kcal/mol
Worst
case
scenario:
ΔGo(Xi)
=
0
&
no
cancellaRon

8. Department
of
Chemistry
8
DFT-­‐D3/
QZVP
HF-­‐3c
(PM6-­‐D3H)
(DFTB2-­‐D3H)
COSMO-­‐RS
Grimme:
DOI:
10.1021/jp411616b
Also:
10.1002/chem.201200497

9. Department
of
Chemistry
9
Changing
protona'on
state
Un-­‐coupled
'tra'on
Coupled
'tra'on

10. Department
of
Chemistry
10
Solva'on
energy
!Gsolv
o
(X) = !Gsolv
o, polar
(X)+!Gsolv
o, non-polar
(X)
= !Gsolv
o, polar
(X)+ !Gsolv
o, exp
(X)!!Gsolv
o, polar
(X)( )
Error
in
data
<
3
kcal/mol
Hydrophic
effect
Error
in
fit
<
3
kcal/mol
X(gas) ! X(aq)
X(gas)+ (H2O)n (liq) ! X(H2O)n (aq)
Explicit
SolvaRon

11. Department
of
Chemistry
11
X(gas)+ (H2O)n (liq) ! X(H2O)n (aq)
X(gas)+ nH2O(liq) ! X(H2O)n (aq)
DOI
10.1021/jp802665d
Solva'on
energy

12. Department
of
Chemistry
PM3:
128
cm-­‐1
(harmonic)
Harmonic
1-­‐D
VSCF
(internal
coords)
Anharmonic
Effects

13. Department
of
Chemistry
!0 = 100 cm"1
Stefan
Grimme
DOI:10.1002/chem.201200497
Anharmonic
Effects

14. Department
of
Chemistry
14
DFT-­‐D3/
QZVP
PM6-­‐D3H
(DFTB2-­‐D3H)
COSMO-­‐RS
Grimme:
DOI
10.1002/chem.201200497
Anharmonic
Effects

15. Department
of
Chemistry
How
bad
is
the
harmonic
approximaRon?
DOI:
10.1021/jp5037537
Anharmonic
Effects
Scaled
frequencies

16. Department
of
Chemistry
16
Anharmonic
Effects
CH4
–
zeolite
binding
1D
(un-­‐coupled)
anharmonic
parRRon
funcRons
DOI
10.1021/ct500291x

17. Department
of
Chemistry
17
Possible
sources
of
error
Imaginary
frequencies
Anharmonic
effects
Ions
Explicit
solvaRon
ConformaRonal
sampling
Changing
protonaRon
state
Explicit
ions

18. Department
of
Chemistry
18
Protein-­‐Ligand
Binding
QM/MM
or
linear
scaling?
HF-­‐3c
PM6-­‐D3H+
DFTB2/3
Low
frequencies
for
constrained
opRmizaRons
COSMO-­‐RS
for
proteins
CaviRes
Explicit
H2O
ConformaRonal
sampling
(PELE)