Doing Chemistry with Computers

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Overview of computational chemistry methods and
applications

• Doing Chemistry with Computers
• Introduction to the tools
• - classical and quantum models
• - dynamics
• - QM/MM computation in complex
• environments
• Applications

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Doing Chemistry with Computers
I.
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Complement and Alternative to Lab Experiments

• investigate unusual temperature/pressure regions
• simulate dangerous experiments
• find alternative for hazardous chemicals
• gain an atomistic description of a reaction
• save lab costs

Understanding of Reaction Mechanism

• characterize reactive intermediates
• identify rate determining or stereoselective
  steps

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Relative Cost of the Most Powerful Commercial
Computer
100
IBM 650
10
1
IBM7094
10-1
Relative Cost per MFLOP
CDC 7600
10-2
CDC 205
10-3
CRAY Y-MP
10-4
SGI/CRAY T3E
10-5
1950
1960
1970
1980
1990
2000
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II.
Computer experiments need models and theories to
describe the laws of nature with the
language of mathematics

• environmental sciences
• biology
• chemistry
• physics
• .

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Simulation Methods for Soft Materials
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When Newton meets Schrödinger...
Sir Isaac Newton
Erwin Schrödinger
(1642 - 1727)
(1887 - 1961)
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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

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Electronic Structure Methods
Classical MD Simulations
Force field approach
Ab-initio approach
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Schrödingers equations made easy with DFT !
Walter Kohn and John Pople Nobelprize in
chemistry 1998
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Mixed Quantum-Classical
Classical MD Simulations
Traditional QC Methods
First-Principles Car-Parrinello MD
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Our needs for a virtual lab

• Atoms

• Electrons

• Eq. of Motion

• Reactions

Density functional theory Car-Parrinello
Molecular Dynamics
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Main idea

• Partitioning the system into
• chemical active part treated by QM methods
• 2. Interface region
• 3. large environment that is modeled by a
  classical force field

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Main idea

• Partitioning the system into
• chemical active part treated by QM methods
• 2. Interface region
• 3. large environment that is modeled by a
  classical force field

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APPLICATIONS
III.
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Improved Optimization Techniques
(simulated annealing)
Nanoscale Silicon Clusters
Si45
Phys.Rev.Lett. 72, 665 (1994)
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In Situ Simulation of Chemical Reactions
ONOOH NO2- ? HNO3 NO2-
Cis/trans isomerization ONOOH
Gas Phase
Aqueous Solution
J. Phys. Chem. A, 104, 6464 (2000)
Chem. Phys. Lett. 297, 205 (1998)
Aqueous Solution
ONOO- ? NO- 1O2
PNAS 97 , 10307 (2000)
ONOO- CO2 ? ?
In collaboration with W. Koppenol, ETH Zurich
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Structure Determination of

Ta Cp (Si(HPh)N(Ar)) - H
2
2
2
2
NMR suggests
asymmetric Tas
TaH 11.63, -1.00 ppm
d
Collaboration with Prof. D. Tilley, University
of California, Berkeley, U.S.A.
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Lowest Energy Structure

• one bridged and

one terminal H

• excellent agreement

with Xray and NMR
Collaboration with Prof. D. Tilley, University
of California, Berkeley, U.S.A.
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Excitation spectra of molecules in
solution Solvent Shift in Aceton
U. Röhrig, A. Laio, J. VandeVondele, J. Hutter,
I. Frank, U.R. (in preparation)
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Anti-AIDS HIV-1 Protease
Molecular Mechanisms of ApoptosisCaspase-3
DNA-Repair Endonuclease IV
Prions and Metal Ions
Selectivity of KcsA Channel
Photoisomerization in Rhodopsin
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Modelling Understanding

• Engineering
• inhibitors
• metal centers
• new residues

• Biomimetics
• easy preparation
• easy handling
• easy tuning

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Rational Design of Biomimetics
Galactose Oxidase
Synthetic Compound
t
i
Stack et al., Science (1999)
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QM/MM Hybrid Car-Parrinello Modeling of GOase
Tyr495
Cu
His496
Cys228
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Parallel Modeling of the Catalytic Cycle
21 kcal/mol
16 kcal/mol
U.R, P. Carloni, K. Doclo and M. Parrinello
JBIC 5, 236 (2000)
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Biomimetic
Goase
U.R, P. Carloni Intl. J. Quant. Chem. 73, 209
(1999)
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Mimetic Stack
GOase
16 kcal/mol
21 kcal/mol
New Biomimetics
M1 16 kcal/mol M2 16 kcal/mol M3 18
kcal/mol M4 14 kcal/mol
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HIV- Virus (AIDS)
HIV- I Protease
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HIV-PR is essential for the formation of
infective viruses
Immature, non-infective Viral particles
Infective viruses
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Viewing Enzymes at work
HIV- I Protease
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Prion Proteins
http\\ www.mad-cow.org
Human Prion Protein
(Wuthrich et al. PNAS 97, 145 (2000))
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Localization of Possible Binding Sites via a
Parallel Statistical and QM Approach

• 111 PDB structures
• ? 2.0 Å resolution
• 216 copper binding sites
• 928 donor atoms

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Secondary structure changes inducedby external
factors (pH, temperature, Cu)
Method Enhanced sampling techniques
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Metal Ion / DNA Interactions
Cis-Pt anticancer drugs
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Metal Ion / DNA Interactions
Cis-Pt anticancer drugs
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Cis/Trans Photoisomerisation in Rhodopsin The
First Steps of Vision
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Cis/Trans Photoisomerisation in Rhodopsin The
First Steps of Vision
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10ns classical MD simulations
total of atoms 24000
? RMS backbone 0.9Å
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Photoisomerisation in the Excited State
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Dynamics in the first excited singlet state
(in collaboration with I. Frank, Univ. Munich, C.
Molteni, Univ. Cambridge, M. Parrinello, CSCS
Manno)
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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