Computer-Aided Design of Metal Ion Hosts

Computer-Aided Design of Metal Ion Hosts

Benjamin P. Hay, 30 April 2003

BattelleU.S. Department of EnergyPacific Northwest National Laboratory

The DOE Legacy - Radioactive Waste

50 years of weapons production:

• Uranium Mining, Milling, and Refinement

• Isotope Separation (Enrichment)

• Fuel and Target Fabrication

• Reactor Operations

• Chemical Separations

• Weapons Component Fabrication

• Weapons Operations

• Research, Development, and Testing

400,000 m3 high-level nuclear waste220,000 m3 TRU waste3.3 million m3 low-level nuclear waste1.4 billion m3 environmental contamination

Data from “Linking Legacies”, DOE/EM-0319, January 1997

Bulk of radioactivity from metals:

Co-60, Sr-90,

Y-90, Tc-99,

Sm-131, Cs-137,

Ba-137, Eu-152,

Eu-154, Eu-155,

Ra-226, Th-230,

U-233, U-235,

U-238, Pu-238,

Pu-239, Pu-240,

Pu-241, Am-241,

Cm-244

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Separations

(1) Initial

(2) After mixing (3) After stripping

SOLVENT EXTRACTIONPROCESS

CC

CC

C CCCC

C C

CC

CCC

C C

CC

CC

C CCCC

(1) Initial

(2) After elution (3) After washing

ION

EXCHANGE

PROCESSC C CC C CC C CC C C

C CC C CC C CC C C

C C CC C CC C CC C C

C


Sensors

ION SELECTIVE ELECTRODE

C C CC C C

V

CC

C C C C

PIEZOELECTRIC CRYSTAL DETECTOR

CCCCC

CC

C CCC

C


Medical Applications

NH HN

N N

O O

OH

OO

HO

HNO

N

HO

O

Detoxification

actinide decorporating agent

N

N N

NO

HO

O

HO

O

OH

O

OH

Diagnostic Imaging

MRI image Gd contrast agent

NN N

O

HO

OOH

OOH

OOH

OOH

Chemotherapy - "Magic Bullets"

monoclonalantibody

linkerchelate

chelate used for Bi-213

M


Hosts for metal ions


N N

O

OHO

HOO

OH

HO

O

N

N

N

N

NH

NH

HNO

HO

HO

O

O

HO

HO

OH

OH

R

R

R

O O

OO

OO

O

O

O

O

O

O

O

O O

O

O O O O

O O

R

R

R

R

O

O

O

O

O O

O

O

O

O

OO

OO

O

N HN

NH N

Host Design

Computer-Aided ?

Guest complexation

Test Performance in actual application

Host synthesisIdentify

candidatestructures

Design criteria

Structural characterizationincluding X-ray analysis

Thermodynamic studies,Binding constant measurement

Computationalscreening

Molecularmodelingmethods


Architecture - scaffolds used to connect sets of binding sites


N N

N N

N

N

N

N

Hg2+/Cu2+ = 5 Cu2+/Hg2+ = 104

OO

O

O O O

O OO

OOO

OO

OO

OO

OO

OO

OO

1010 106 105 103

Structure can have a large effect on binding affinity:

and a large effect on selectivity:

Structural effects are often difficult to predict


How do we approach this problem?

O O

OO

O O

OOM+ Mn+

n+

O O

OO

O O

OOM+ M(OH2)6

n+

n+

OH2

OH2

+ 2 H2O

conformationalreorganization

metal ion complexation

+

free form binding form bound form


Electronic structure calculations


Force field calculations are much, much quicker

-40

-30

-20

-40 -30 -20M M k c a l / m o l

QM kcal/mol

0.05 Å

0.17 Å

0.19 Å

MM3 calculations take only 15 seconds/structure on a laptop computer


Downside - MM models often require parameterization

ether donors

arene donors

High–level electronic structure calculations on simple analogs

Crystal structure data

0.29 Å

0.29 Å

0.25 Å0.23 Å


Extending MM3 models for f-element complexes

HOPO[U(L)4(SCN)4]

amide

[Gd(L)(OH2)2]

0.19 Å0.14 Å

amine

[Pu(L)2(NO3)2]2+

0.25 Å

pyridine N-oxide

phosphine oxidecarboxylate

[Nd(L)(OH2)3]–

0.17 Å


What can we learn by examining host structures?

15-crown-5Na+

18-crown-6K+Li+

12-crown-4


Binding site geometry in crowns favors large metals


Na+ K+Li+

bindingform

boundform

Size–match is not sufficient for a good fit


good donororientation

bad donororientation

12-crown-4 versus 14-crown-4


Ligand strain energy

free

binding

bound

² U1

² U2

² Utot = ² U1 + ² U2

complex


Binding affinity vs. host strain

2

4

6

8

10

12

14

16

0 2 4 6 8 10 12

1

23

4 5

6

7

8

OO

OO

OOO O

OOO

OO

OO

O OO

OOO

OO

O

OOO

O

O

O

OO

O O

O

O

2

OO

O

OO

O

OO

OO

OO

6

4

7 8

1 3

5

² Utot, kcal/mol

l o g K e q ( N a + c o m p l e x a t i o n )


Another example

-25

-20

-15

-10

-5

60 70 80 905

O

O OO

ONH HN HNO

HO

HO

O O

OH

OH

OH

OH

N N NO

HO

HO

OO

OH

OH

OH

OH

NH

NH

HNO

HO

HO

O

O

HO

HO

OH

OH

R

R

R

1

234

R = HR = MeR = Et

l o g K e q ( F e 3 + c o m p l e x a t i o n )

² Utot, kcal/mol


Actinide sequestering agents

P

O

OO

O

PUREX agent

Selective removal of Pu and U from spent fuel is done via solvent extraction:

Used at Hanford from 1956 through 1987

Currently used for reprocessing power reactor fuel in France, UK, Japan, and Russia.

P

OO

N

OO

N N

DIAMEX agent (Numatec)TRUEX agent (ANL/Eichrom)

Agents that also remove Am(III) and Cm(III):


A closer look at the malonamide architecture

optimal

orientation

free form

binding form

bound form

3.0 kcal/mol

2.5kcal/mol

5.5kcal/mol


Improved architecture?

NN

OO

MeMe

H

H

NN

OO

MeMe

H

H

² Utot = 0.0 kcal/mol

² Utot = 0.1 kcal/mol

X-ray structure of [Eu(L)2(NO3)3]trans

cis


Proof in the pudding . . .

10-6

10-4

10-2

100

102

104

0.0001 0.001 0.01 0.1 1

1

2NN

OO

NN

OO

1

2

Extraction into t-butylbenzene from aqueous solution

containing 1 M NaNO3, 1.5 mM HNO3, 0.1 mM

Eu(N03)3, and 1-µL of 155Eu tracer solution.

D E u

[ligand], mol•lit-1

10 million times more effective


Structural design criteria

ether

amide

aryl ether

catecholate

arene

amine

HOPO

pyridine N-oxide

phosphine oxide


Structural design is a trial–and–error process

Problem: you have to build structures before you can test them.


Computer–Aided Host Design

Guest complexation

Test Performance in actual application

Host synthesisIdentify

candidatestructures

Design criteria

Structural characterizationincluding X-ray analysis

Thermodynamic studies,Binding constant measurement

Computationalscreening

Molecularmodelingmethods

StructureGenerator


Structure-Based Drug Design

Known host structure• steric constraints• H-bond regions• hydrophobic regions

Step 1: Build candidate guests•position functional groups•link with spacer fragments

Step 2: Score the candidates•number of H-bonds•hydrophobic contact area•entropic factors•conformational strain energy


Structure-based host design?

Li–O distance – 2.1 Å

6-coordinate Li+ complex

OLi

O

OLi

O

O Li

O

O

O

O+

OLi

O O

O

OLi

O O

O

OLi

O O

O

+ OLi

O

ether binding sites

O+O

Step 1: building Step 2: scoring

geometryevaluation

strain analysis

QM analysis

conformationalanalysis


HostDesigner Software

+

Objectives:

Score structures with respect to how well they complement the guest.

Build structures by connecting host fragments with linking fragments• examine all possible connectivities • examine all conformations for each connectivity

Do it quickly.


LINKER algorithm

(1) Define two host fragments

(2) Choose a potential link

(3) Bond 1st fragment to link

(4) Set dihedral angle on bond

(5) Bond 2nd fragment to link

(6) Set dihedral angle on bond


Scoring by geometry

0.50 Å 4.50 Å 6.35 Å3.42 Å

6.84 Å 6.89 Å 7.64 Å

8.20 Å

6.59 Å

generates 81 structures from methylene linkage

finds only 9 unique structures rejected


Linking fragment database

NULL

etc ...


CnHm for n = 0 - 6 (excluding alkynes, 3-membered rings, and 4-membered rings)

Menull


Dimethylated 5– and 6–membered rings


Selected fused–rings

cis/trans

cis/trans cis/trans

total: 20,094 linking structures


Example of a LINKER run


1 2

3 4

5 6

Input:

Output: 1,242,037 host

structures in 8.0 sec

(MacOS, 800 MHz)

155,255 structures/sec ! ! !

Validation

Are the structures generated by HostDesigner accurate?

optimize- M

optrmsd

Do the structures complement the metal ion?

- M

opt

optimize

² U


How did we do?

1 2

3 4

5 6

host

1

2

3

4

5

6

(Å)

0.12

0.11

0.09

0.08

0.10

0.11

(kcal/mol)

0.23

0.21

0.10

0.10

0.08

0.14

² Urmsd


Second generation


1 2

3 4

2 x

Output: 5,802,532 host

structures in 39 sec

(MacOS, 800 MHz)

Input:

OVERLAY algorithm

etc . . .


Tetradentate ether macrocycles

0.3 kcal/mol

O

OO

O

O

OO

O

designed by computer

0.3 kcal/mol

O

OO

O R

RR

R

RR

R R

4.3 to 6.8 kcal/mol

designed by humans

R

O O

O O

7.7 kcal/mol


Applications in progressCs, Sr, Ra – ethers, arenes

Dr. Bruce Moyer, ORNL

Actinides – amidesProf. Jim Hutchison, UO

Actinides - phosphoryl + N-oxidesProf. Robert Paine, UNM

Actinides -catecholatesProf. Ken Raymond, UC–Berkeley

++

+

+ +

+


HostDesigner software

ORNLBruce A. Moyer

U of OregonJames E. HutchisonTimothy J. R. WeakleyRobert D. Gilbertson

UC- BerkeleyKenneth N. Raymond

U of New MexicoRobert T. Paine

Structure-function research, scoring methods, and applications

PNNLTimothy K. Firman (PD)Bert deJongJohn B. Nicholas

SponsorsLDRD program, PNNL and the Office of Chemical Science, Basic Energy Sciences, Office of Science

PNNLCalvin C. AinsworthDave A. DixonDave FellerJorge Garza (VS)Gregg J. LumettaBrian M. RapkoJamal Uddin (PD)Rubi Vargas (PD)Cungen Zhang (PD)

EMSL - supercomputer

SponsorEnvironmental Management Science Program, Office of Science, Office of Environmental Management, Project Nos. 54679, 55087, 64974, 73759, 82773


Further information


Hay, B. P.; Firman, T.K. “HostDesigner: A Program for the de Novo Structure-Based Design of Molecular Receptors with Binding Sites that Complement Metal Ion Guests.” Inorg. Chem. 2002, 41, 5502.

HostDesigner Software

http://hostdesigner.emsl.pnl.gov

Hay, B. P.; Hancock, R. D. Coord. Chem. Rev. 2001, 212, 61.

Lumetta, G. J.; Rapko, B. M.; Garza, P. A.; Hay, B. P.; Gilbertson, R. D.; Weakley, T. J. R.; Hutchison, J. E. J. Am. Chem. Soc., Comm. Ed. 2002, 124, 5644.

Amides

Ethers

Computer-Aided Design of Metal Ion Hosts

Documents

host structures

host strainbenjamin

host designcomputer

ion exchange processes

binding affinity

improved architecture

structural effects

architecture scaffolds