predicting accurate absolute binding energies in aqueous solution: thermodynamic considerations for...
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Department of Chemistry
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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
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DFT-‐D3/ QZVP
HF-‐3c (PM6-‐D3H) (DFTB2-‐D3H)
COSMO-‐RS
Grimme: DOI 10.1021/jp411616b Also: DOI 10.1002/chem.201200497
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DFT-‐D3/ QZVP
HF-‐3c (PM6-‐D3H) (DFTB2-‐D3H)
COSMO-‐RS
Grimme: DOI 10.1021/jp411616b Also: 10.1002/chem.201200497
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3-‐body dispersion & RRHO crucial
DFT-‐D3/ QZVP
PM6-‐D3H (DFTB2-‐D3H) COSMO-‐RS
Grimme: DOI 10.1002/chem.201200497
MAD: 2 kcal/mol
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Possible sources of error
Imaginary frequencies
Anharmonic
effects
Ions
Explicit solvaRon
ConformaRonal sampling
Changing
protonaRon state
Explicit ions
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Conforma'onal Sampling
Must find lowest Go conformaRon (duh)
Must find all low-‐Go conformaRons?
Nconf
kcal/m
ol
Worst case scenario: ΔGo(Xi) = 0 & no cancellaRon
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DFT-‐D3/ QZVP
HF-‐3c (PM6-‐D3H) (DFTB2-‐D3H)
COSMO-‐RS
Grimme: DOI: 10.1021/jp411616b Also: 10.1002/chem.201200497
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Changing protona'on state
Un-‐coupled 'tra'on
Coupled 'tra'on
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Solva'on energy
!Gsolvo (X) = !Gsolv
o, polar (X)+!Gsolvo, non-polar (X)
= !Gsolvo, polar (X)+ !Gsolv
o, exp (X)!!Gsolvo, 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
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X(gas)+ (H2O)n (liq)! X(H2O)n (aq)
X(gas)+ nH2O(liq)! X(H2O)n (aq)
DOI 10.1021/jp802665d
Solva'on energy
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PM3: 128 cm-‐1 (harmonic)
Harmonic
1-‐D VSCF (internal coords)
Anharmonic Effects
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! 0 = 100 cm"1
Stefan Grimme DOI:10.1002/chem.201200497
Anharmonic Effects
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DFT-‐D3/ QZVP
PM6-‐D3H (DFTB2-‐D3H) COSMO-‐RS
Grimme: DOI 10.1002/chem.201200497
Anharmonic Effects
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How bad is the harmonic approximaRon?
DOI: 10.1021/jp5037537
Anharmonic Effects
Scaled frequencies
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Anharmonic Effects
CH4 – zeolite binding 1D (un-‐coupled) anharmonic
parRRon funcRons
DOI 10.1021/ct500291x
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Possible sources of error
Imaginary frequencies
Anharmonic
effects
Ions
Explicit solvaRon
ConformaRonal sampling
Changing
protonaRon state
Explicit ions
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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)