host-guest ligand binding systemschemie keywords: enthalpy/entropy compensation · enzyme catalysis...
TRANSCRIPT
Host-Guest LigandBinding Systems
Ponder Lab Group MeetingDecember 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
Solvent CB7 Ligand vdW Electrostatic Restraint
Abound Asolv
Double Decoupling with a Restraining Potential
Solvent CB7 Ligand vdW Electrostatic Restraint
Abound
Asolv
+Ures ele = 1 0 vdW = 1 0 Ures
ele = 1 0 vdW = 1 0
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
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
Ures (r) = k(r r0 )2
Uij = 5ij
1.077
0.7(1 )2 + ( + 0.07)7
1.120.7(1 )2 + ( +1.12)
2
SAMPL CB7 Overall Results -17
-15
-13
-11
-9
-7
-5
-3
-1
-17 -15 -13 -11 -9 -7 -5 -3 -1
Experimental Free Energy Values (kcal/mol)
Com
pute
d Fr
ee E
nerg
y Va
lues
(kca
l/mol
)
Statistics: Average Signed Error = 0.66 kcal/mol Average Unsigned Error = 1.69 kcal/mol RMS Error = 2.27 kcal/mol Kendall Tau = 0.62 R-value = 0.82 1:1
-17
-15
-13
-11
-9
-7
-5
-3
-1
-17 -15 -13 -11 -9 -7 -5 -3 -1
Reasonable Binding Estimates
Experimental Free Energy Values (kcal/mol)
Com
pute
d Fr
ee E
nerg
y Va
lues
(kca
l/mol
)
1:1
-17
-15
-13
-11
-9
-7
-5
-3
-1
-17 -15 -13 -11 -9 -7 -5 -3 -1
Overpredicted as Tight Binders
Experimental Free Energy Values (kcal/mol)
Com
pute
d Fr
ee E
nerg
y Va
lues
(kca
l/mol
)
1:1
-17
-15
-13
-11
-9
-7
-5
-3
-1
-17 -15 -13 -11 -9 -7 -5 -3 -1
Underpredicted as Loose Binders
Experimental Free Energy Values (kcal/mol)
Com
pute
d Fr
ee E
nerg
y Va
lues
(kca
l/mol
)
1:1
Lessons from Free Energy Prediction
Critical aspects for binding calculations:
Force field accuracy
Sampling method / efficiency
Binding mode
Salt effects / pH
Periodic boundary effects / Size dependence
Thermodynamic Organic Complexes
Binding Affinities of Host–Guest, Protein–Ligand, andProtein–Transition-State ComplexesK. N. Houk,* Andrew G. Leach, Susanna P. Kim, and Xiyun Zhang
AngewandteChemie
Keywords:binding affinities · enthalpy/entropycompensation · enzyme catalysis ·host–guest systems ·solvent-accessiblesurface area
In memory of Donald J. Cram
K. N. Houk et al.Reviews
4872 � 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/anie.200200565 Angew. Chem. Int. Ed. 2003, 42, 4872 – 4897
Supramolecular ChemistryDOI: 10.1002/anie.200802947
Binding Mechanisms in Supramolecular ComplexesHans-J�rg Schneider*
AngewandteChemie
Keywords:drug design · host–guest systems ·noncovalent interactions ·reaction mechanisms ·supramolecularchemistry
H.-J. SchneiderReviews
3924 www.angewandte.org � 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2009, 48, 3924 – 3977
Ligand Binding Energies
Understanding Noncovalent Interactions: LigandBinding Energy and Catalytic Efficiency from Ligand-Induced Reductions in Motion within Receptors andEnzymesDudley H. Williams,* Elaine Stephens, Dominic P. O�Brien, and Min Zhou
AngewandteChemie
Keywords:enthalpy/entropy compensation ·enzyme catalysis · non-covalent interactions ·receptors · signaltransduction
D. H. Williams et al.Reviews
6596 � 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/anie.200300644 Angew. Chem. Int. Ed. 2004, 43, 6596 – 6616
Molecular Recognition
Quantifying Intermolecular Interactions: Guidelines forthe Molecular Recognition ToolboxChristopher A. Hunter*
AngewandteChemie
Keywords:formation enthalpy · hydrogen bonds ·molecular recognition · solventeffects · statistical thermo-dynamics
Dedicated to Professor Dudley H. Williams
C. A. HunterReviews
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 thatare complimentary in structureto the activiated complexes ofthe reactions that they catalyze... [rather than] entering intoreactions.”
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