Overview of computational chemistry methods and applications

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Doing Chemistry with Computers



Introduction to the tools


-

classical and quantum models


-

dynamics


-

QM/MM: computation in complex


environments



Applications



Overview of computational chemistry


methods and applications

Doing Chemistry with Computers

I.


investigate unusual temperature/pressure regions


simulate dangerous experiments


find alternative for hazardous chemicals


g
ain an at
o
mistic description of
a reaction


save lab costs


Why Do Computer Experiments?

Complement and Alternative to Lab Experiments

Understanding of Reaction Mechanism



characterize reactive intermediates



identify rate determining or stereoselective steps



optimization of catalysts



rational drug design



controlling and tuning of chemical reactions

1950

1960

1970

1980

1990

2000

100

10
-
1

10

1

10
-
2

10
-
3

10
-
4

IBM 650

CDC 7600

IBM7094

CRAY Y
-
MP

CDC 205

Relative Cost per MFLOP

Relative Cost of the Most Powerful
Commercial Computer

10
-
5

SGI/CRAY T3E

Computer experiments need

models and theories

to describe the laws of nature





with the language

of

mathematics



environmental sciences


biology


chemistry


physics


….


II.

Simulation Methods for Soft Materials

When Newton meets Schrödinger...

ma
F





H
ˆ
Sir Isaac Newton

(1642
-

1727)

Erwin Schrödinger

(1887
-

1961)

Computational Chemistry and Biology

Electronic Structure

Methods

Classical MD

Simulations



parameter
-
free MD



ab initio force field



no transferability


problem



chemical reactions



improved optimization



finite T effects



thermodynamic &


dynamic properties



solids & liquids

Computational Chemistry and Biology

Electronic Structure

Methods

Classical MD

Simulations

Force field approach

Ab
-
initio approach

Walter Kohn and John Pople

Nobelprize in chemistry 1998

Schrödingers equations made easy with DFT !

Traditional QC

Methods

First
-
Principles

Car
-
Parrinello

MD

Classical MD

Simulations

When Quantum Chemistry Starts to Move...

Mixed
Quantum
-
Classical

Our needs for a virtual lab


Electrons


Eq.
o
f Motion



Reactions


Atoms

Density functional theory & Car
-
Parrinello
Molecular Dynamics


Mixed Quantum
-
Classical

in a complex environment
-

QM/MM


Main idea

Partitioning

the system into


1.
chemical active

part

treated by QM methods


2.

Interface region


3.


large
environment

that is
modeled by a classical
force field

QM

interface

Classical MM

Mixed Quantum
-
Classical

in a complex environment
-

QM/MM


Main idea

Partitioning

the system into


1.
chemical active

part

treated by QM methods


2.

Interface region


3.


large
environment

that is
modeled by a classical
force field

QM

interface

Classical MM

APPLICATIONS

Phys.Rev.Lett.

72, 665 (1994)

III.

Improved Optimization Techniques:

(simulated annealing)

Nanoscale Silicon
Clusters

Si
45

2
C
2

Li

H
2

Li

Li

C

C

H

H

Phys.Rev.Lett. 72, 665 (1994)

Li

Li

C

C

H

H

J. Am. Chem. Soc. 177, 42 (1995)

In Situ

Simulation of Chemical Reactions

Chem. Phys. Lett. 297, 205 (1998)

.
OH +
.
NO
2

ONOOH

Gas Phase

Aqueous Solution

J. Phys. Chem. A,

104, 6464 (2000)

Cis/trans

isomerization ONOOH

ONOOH + NO
2
-




䡎伳O⬠乏
2
-

Aqueous Solution

ONOO
-



NO
-

+
1
O
2

PNAS
97 , 10307 (2000)



ONOO
-

+ CO
2



?

In collaboration with W. Koppenol, ETH Zurich

Pd
Si
Si
Cl
Cl
Cl
Cl
Cl
Cl
P
Fe
Homogeneous Catalysis

Organo

Lithium

Pd
-
Phosphine


Ta
2
-
Hydride


Pd(ll)
-
bis(trichlorosilyl)

Re,Tc
-
Thioether


W
2
Cl
2
(PMe
3
)
2
(NHR)
2


Structure Determination of

Collaboration with Prof. D. Tilley, University of California, Berkeley, U.S.A.

Ta Cp (Si(HPh)N(Ar))
-

H

2

2

*

2

2

NMR suggests

asymmetric Ta’s

TaH 11.63,
-
1.00 ppm

d

Lowest Energy Structure:

Collaboration with Prof. D. Tilley, University of California, Berkeley, U.S.A.



one bridged and





excellent agreement

with Xray and NMR

one terminal H

Excitation spectra of molecules in
solution;

Solvent Shift in Aceton

n
-
>
p
*

卯汶p湴n卨楦琺p†††
〮0ㄠ1嘠V

⡥(瀩p††
〮0㍥嘠

⡒佋匬p免㴠卯汵瑥t

D

= 0.03
-
0.04eV

(ROKS, QM = Solute


+ 12 H
2
O)

U. Röhrig, A. Laio, J. VandeVondele, J. Hutter, I. Frank, U.R. (in preparation)

Anti
-
AIDS:

HIV
-
1 Protease

Prions


and

Metal Ions

DNA
-
Repair:

Endonuclease IV

Photoisomerization

in Rhodopsin

Molecular Mechanisms

of Apoptosis:Caspase
-
3

Selectivity of

KcsA Channel

Ab initio Modelling of Enzymes


Rational Design of Biomimetics & Enzyme
-
Engineering

Biomimetics



easy preparation



easy handling



easy tuning


Engineering



inhibitors




metal centers



new residues


Modelling

&

Understanding

Rational

Design

of Biomimetics

Galactose Oxidase

O
N
O
N
C
u
R
5
R
3
R
3
R
5
Synthetic Compound

t


i


R
3


= SPh, SPr , Bu , Br

R
5


= Bu , Br

t




R
-

H
2
C
-

OH + O
2

R
-
C + H
2
O
2



O

H

Stack et al., Science (1999)


QM/MM Hybrid Car
-
Parrinello


Modeling of GOase

Cu

Tyr495

Cys228

His496

U.R, P. Carloni, K. Doclo and M. Parrinello JBIC 5, 236 (2000)

Parallel Modeling of the Catalytic Cycle

resting state

inactive

GOase

Mimic

GOase

resting state

active

Mimic

after proton

transfer

transition state


H
-
abstraction

16 kcal/mol

21 kcal/mol

Biomimetic

Goase

U.R, P. Carloni Intl. J. Quant. Chem. 73, 209 (1999)

GOase

Mimetic

Stack

New Biomimetics

M1: 16 kcal/mol

M2: 16 kcal/mol

M3: 18 kcal/mol

M4: 14 kcal/mol

16 kcal/mol

21 kcal/mol

HIV
-

Virus (AIDS)

HIV
-

I Protease

Asp25

Asp25’

Gly27

Gly27’

Thr26

Thr26’

HIV
-
PR is essential for the
formation of infective viruses

Immature, non
-
infective

Viral particles

HIV
-
1 PR

Infective viruses

Viewing Enzymes

at work

HIV
-

I Protease


Prion Proteins


Fatal Neurodegenerative

Diseases:


Mad Cow Disease (BSE)



Scrapie



Creutzfeldt
-
Jakob



caused by abnormal


isoform PrP(Sc)

Human Prion Protein

(Wuthrich et al. PNAS 97, 145 (2000))

http:
\
\

www.mad
-
cow.org

Localization of Possible Binding Sites via
a Parallel Statistical and QM Approach



111 PDB structures




㈮〠씠牥獯汵瑩潮



216 copper binding sites



928 donor atoms

0
10
20
30
40
50
60
70
H
C
M
G
D
Y
E
Q
S

Cu
-
coordinated

Natural
abundance

His 187

Met 206

Tyr 157

R = 24

His 140

Asp 147

Asp 144

R = 21

His 140

Asp 147

Asp 144

R = 21

His 140

Asp 147

Asp
144

R = 21

Secondary structure changes induced

by external factors

(pH, temperature, [Cu++])

Method: Enhanced sampling techniques


Metal Ion / DNA Interactions

Cis
-
Pt anticancer drugs

Metal Ion / DNA Interactions

Cis
-
Pt anticancer drugs

A piano chair


to fight cancer

Organoruthenium anticancer drugs

(in collaboration with

Prof. Paul Dyson, EPFL)

Cis/Trans Photoisomerisation in Rhodopsin:

The First Steps of Vision

200fs

0.67

Cis/Trans Photoisomerisation in Rhodopsin:

The First Steps of Vision

200fs

0.67

10ns classical MD simulations



RMS backbone: 0.9Å

total # of atoms: 24000

Photoisomerisation in the Excited State

Dynamics in the first excited singlet state

(in collaboration with I. Frank, Univ. Munich, C. Molteni,

Univ. Cambridge, M. Parrinello, CSCS Manno)

Not all chemists wear white coats...

Computer Experiments




provide atomistic picture of (bio)chemical systems



help to characterize and understand reaction mechanisms



planning of laboratory experiments



computational modelling of catalysts and enzymes



rational design of drugs and biomimetics

Current Limits and Future Perspectives




accuracy of electronic structure method



system size



limited time scale



improved QM/MM methods



long time scale techniques