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