Host-Guest Ligand
Binding Systems
Ponder Lab Group Meeting
December 3, 2014
Cucurbit[7]uril Parameterization
DMA on MP2/6-311G(1d,1p) Density on CB5
Potential fit to MP2/6-311++G(2d,2p)
MDQµ Fit = 0.147, Partial Charge Fit = 0.811
Absolute Free Energy of Binding
Abind = Abound
Asolv
Abound
Solvent
Asolv
CB7
Ligand
vdW
Electrostatic
Restraint
Double Decoupling with
a Restraining Potential
+U res
ele
=1
0
=1
0
vdW
=1
0
U res
Abound
Asolv
ele
Solvent
=1
0
CB7
vdW
Ligand
vdW
Electrostatic
Restraint
Calculation Protocol
Double decoupling molecular dynamics simulations
Explicit water solvent (40A box)
Free energy estimation by Bennett Acceptance Ratio
Canonical ensemble (298K, 1-3ns trajectories per value)
Restraining potential applied to bound decoupling simulations
U res (r) = k(r r0 )2
k = 15 kcal mol-1 A-2; r = center-of-mass distance; r0 =
average center-of-mass distance obtained from unrestrained
bound simulations
Soft-core buffered 14-7 vdW potentials
U ij =
5
ij
0.7(1
1.07 7
)2 + ( + 0.07)7
0.7(1
1.12
2
2
) + ( + 1.12)
Computed Free Energy Values (kcal/mol)
SAMPL CB7 Overall Results
-17
Statistics:
-15
Average Signed Error = 0.66 kcal/mol
-13
Average Unsigned Error = 1.69 kcal/mol
-11
RMS Error = 2.27 kcal/mol
-9
Kendall Tau = 0.62
-7
-5
R-value = 0.82
1:1
-3
-1
-1
-3
-5
-7
-9
-11
-13
-15
Experimental Free Energy Values (kcal/mol)
-17
Reasonable Binding Estimates
Computed Free Energy Values (kcal/mol)
-17
-15
-13
-11
-9
-7
-5
1:1
-3
-1
-1
-3
-5
-7
-9
-11
-13
-15
Experimental Free Energy Values (kcal/mol)
-17
Overpredicted as Tight Binders
Computed Free Energy Values (kcal/mol)
-17
-15
-13
-11
-9
-7
-5
1:1
-3
-1
-1
-3
-5
-7
-9
-11
-13
-15
Experimental Free Energy Values (kcal/mol)
-17
Underpredicted as Loose Binders
Computed Free Energy Values (kcal/mol)
-17
-15
-13
-11
-9
-7
-5
1:1
-3
-1
-1
-3
-5
-7
-9
-11
-13
-15
Experimental Free Energy Values (kcal/mol)
-17
Lessons from Free Energy Prediction
&ULWLFDO Dspects for ELQGLQJ calculations:
Force field DFFXUDF\
Sampling method / efficiency
Binding mode
Salt effectV S+
Periodic boundary effectV 6L]H GHSHQGHQFH
Reviews
K. N. Houk et al.
Thermodynamic Organic Complexes
Binding Affinities of Host–Guest, Protein–Ligand, and
Protein–Transition-State Complexes
K. N. Houk,* Andrew G. Leach, Susanna P. Kim, and Xiyun Zhang
Keywords:
binding affinities · enthalpy/entropy
compensation · enzyme catalysis ·
host–guest systems ·
solvent-accessible
surface area
In memory of Donald J. Cram
Angewandte
Chemie
4872
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200200565
Angew. Chem. Int. Ed. 2003, 42, 4872 – 4897
Reviews
H.-J. Schneider
Supramolecular Chemistry
DOI: 10.1002/anie.200802947
Binding Mechanisms in Supramolecular Complexes
Hans-Jrg Schneider*
Keywords:
drug design · host–guest systems ·
noncovalent interactions ·
reaction mechanisms ·
supramolecular
chemistry
Angewandte
Chemie
3924
www.angewandte.org
2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 3924 – 3977
Reviews
D. H. Williams et al.
Ligand Binding Energies
Understanding Noncovalent Interactions: Ligand
Binding Energy and Catalytic Efficiency from LigandInduced Reductions in Motion within Receptors and
Enzymes
Dudley H. Williams,* Elaine Stephens, Dominic P. OBrien, and Min Zhou
Keywords:
enthalpy/entropy compensation ·
enzyme catalysis · noncovalent interactions ·
receptors · signal
transduction
Angewandte
Chemie
6596
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200300644
Angew. Chem. Int. Ed. 2004, 43, 6596 – 6616
Reviews
C. A. Hunter
Molecular Recognition
Quantifying Intermolecular Interactions: Guidelines for
the Molecular Recognition Toolbox
Christopher A. Hunter*
Keywords:
formation enthalpy · hydrogen bonds ·
molecular recognition · solvent
effects · statistical thermodynamics
Dedicated to Professor Dudley H. Williams
Angewandte
Chemie
5310
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200301739
Angew. Chem. Int. Ed. 2004, 43, 5310 – 5324
Cyclodextrins: α-, β- and γ-Forms
α-Cyclodextrin + p-Hydroxybenzoic Acid
Cyclodextrin Ligand Binding Distribution
Binding Constants by System Type
Binding Constants by System Type
“Enzymes are molecules that
are complimentary in structure
to the activiated complexes of
the reactions that they catalyze
... [rather than] entering into
reactions.”
Linus Pauling,
The Nature of Forces between Large
Molecules of Biological Interest,
Nature 161, 707-709 (1948)
Binding vs Buried Surface Area
Williams’ Magic Binding Formula
Translation-Rotation Energy Penalty
Binding to Vancomycin/Ristocetin A