Materiale didattico:

http://dolly.dscg.unimore.it/2016/

Molecular Modelling for Beginners

Alan Hinchliffe
2003-Wiley-VCH

Molecular Modeling
Principles and applications
Andrew R. Leach
1
2001-Prentice Hall
Teaching methods
Lectures
Computational chemistry exercises
Homework
end of lectures quiz

Assessment
Assignments
End of course exam
Evaluation Criteria:
Assignments

c1 capacit di applicare quanto studiato al proprio caso di studio 3.5

c2 capacit di presentare i dati e discutere i propri elaborati 3
c3 qualit dei testi scritti (propriet di linguaggio e chiarezza 3
espositiva);
c4 puntualit nelle consegne 0.5
Computational Chemistry
Computational Chemistry is the modeling of chemical
phenomenon using computers rather than chemicals.

The models used vary in their sophistication:

Chemoinformatics

Molecular mechanics

Semi-empirical methods

Ab initio quantum chemistry

All these methods, except the last, rely on empirical

information (parameters, energy levels etc).

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Accurate calculation is not
synonymous to useful
interpretation.
To calculate a molecule is
not to understand it.

Parr, R. G. in Density Functional

Methods in Physics, Editors : R. M.
Dreizler and J. da Providencia,
Plenum, 1985, p. 141.

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 Ab initio quantum chemistry

Ab initio means from the beginning or from first principles, i.e. quantum
mechanics.

Discovered (c.a.1925). Extremely general, applies to all atomic-scale objects.

According to history, Schrdinger first wrote down

his wave equation during a skiing Christmas
holiday in 1925-26.

Work of many distinguished scientists.

Page from Schrdinger's

notebook where he first
wrote his wave equation
7
 1926
Schrdinger Heisenberg

Meccanica Meccanica delle

Ondulatoria Matrici

Meccanica Quantistica
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 Ab initio quantum chemistry

The general theory of quantum mechanics is

now almost complete.

The fundamental laws necessary for the

mathematical treatment of a large part of
physics and the whole of chemistry are thus
completely known, and the difficulty lies
only in the fact that application of these laws leads to
equations that are too complex to
be solved.

P.A.M. Dirac, 1929

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Ab initio quantum chemistry

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 QUANTUM SCALE
Electronic Structure Methods
Molecule is just Nuclei and electrons are mixed up as Soup
electrons in a box Bonding is only interpretation
problem
Require no empirical parameters

Molecule is described by wave function or electron density

To know the properties of these electrons, we probe the wave

function with appropriate operator.

The Schrdinger equation

H E
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The chemical connection
H E
Besides the total energy of the system,
many chemical properties can be obtained from derivatives
of the energy with respect to some external parameter.
Examples of external parameters include:
Geometric parameters (bond lengths, angles etc.).
Applied electric fields (e.g. from a solvent)
Magnetic field (in NMR experiments).
1st and 2nd derivatives are commonly available and used.
Higher derivatives are required for some properties, but
are expensive (and difficult!) to compute

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Over the last four decades powerful molecular
modelling tools have been developed which are
capable of accurately predicting properties of
molecules.

These developments have come about largely due to:

-The dramatic increase in computer speed.

-The design of efficient quantum chemical algorithms

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Goal: Insight into chemical phenomena.

Molecular Transition States

properties Reaction coords.

Ab initio electronic structure theory

Hartree-Fock (HF) Spectroscopic
Electron Correlation (MP2, CI, CC, etc.) observables

Geometry Prodding
prediction Experimentalists
Benchmarks for
parameterization
The work behind this years Nobel Prize
has opened up a fruitful cooperation
between theory and experiment that has
made many otherwise unsolvable
problems solvable.
COMPUTABLE PROPERTIES

Many molecular properties can be computed, these include:

Bond energies and reaction energies

Structures of ground-, excited- and transition-states
Atomic charges and electrostatic potentials
Vibrational frequencies (IR and Raman)
Transition energies and intensities for UV and IR spectra
NMR chemical shifts
Dipole moments, polarisabilities and hyperpolarisabilities
Reaction pathways and mechanisms
 What Properties can be Calculated?
Equilibrium structures
Transition State structures
Microwave, NMR spectra
Reaction energies
Reaction barriers
Dissociation energies
Charge distributions
Reaction Rates
Reaction Free Energies
Circular Dichroism (optical, magnetic, vibrational)
Spin-orbit couplings
Full relativistic energies
Excited States (vertical)
Solvent Effects
pKas
Density matrix methods/geminals
Linear Scaling (ie of the methods with number of electrons/basis functions)
Local correlation methods
Accurate enzyme-substrate interactions
Crystal structures (prediction)
Melting points
Protein folding
Full reaction dynamics
Molecular dynamics
Solvent dynamics
Systematic improvements of DFT
Excited States (adiabatic)
What Properties can be Calculated?
In order of difficulty:

Molecular Structures (+/ 1%)

Reaction Enthalpies (+/ 2 kcal/mol)
Vibrational Frequencies (+/ 10%)
Reaction Free Energies (+/ 5 kcal/mol)
Infrared Intensities (normally not too bad for fundamentals)
Dipole Moments (depends)
Reaction Rates (errors vary enormously)
 Structure
Chemistry and Biochemistry have developed very rapidly during the last 50 years.
The development of Biochemistry is perhaps the most striking one.

In the first half of these 50 years the determination of protein structure was the field
where the largest efforts were spent and the largest progress was made.
The standard methods to analyse the structure of proteins are X-ray crystallography of crystals
or NMR-spectroscopy.

What is perhaps less well known is that in the computer programs that are used to analyse the
diffraction pattern from an X-ray investigation or the spin-spin couplings obtained from a NMR
experiment there is hidden a computer code that calculates the energy of the considered
structure based on empirically and theoretically obtained potentials describing the interaction
between the atoms in the system.

The reason for this is that there is not enough experimental information to uniquely
determine the structure of the studied system.

This is just one of the aspects of how computers and theoretical models have become
essential tools for the experimental chemist.
Single crystal
Sperm whale myoglobin
 Come si ottiene la struttura NMR di
macromolecole?
Preparare del campione 1.5mM 600 ml

Acquisire spettri (HSQC) etc

Assegnare backbone Assegnare catene laterali

TOCSY 2D
CbCaNH, CbCa(CO)NH,
H(C)CH-TOCSY
HNHA
(HN, N, Ca, Cb, Ha) (H)CCH-TOCSY
NOESY 2D
15N/13C NOESY-HSQC
Assegnazione sequenziale del backbone
Assegnazione NOE
 15N-HSQC E/ZnE133QM2SOD
15N

1H
 Come usiamo queste informazioni?

Angoli CHI e PSI Assegnamento NOE

HNHA
15N-NOESY-HSQC
Integrazione

Distanze (CALIBA)

Calcolo struttura (DYANA)

Refinement (AMBER)

Analisi della struttura (PROCHECK)

 Reactivity
Today the focus of chemical research is much more on function than on structure.
Chemists ask questions like How does this happen? rather than What does this look like? .

Questions about function are generally difficult to answer using experimental techniques.

Isotope labelling and femtosecond spectroscopy can give clues, but rarely produce conclusive
evidence for a given mechanism in systems with the complexity characterizing many catalytic
chemical processes and almost all biochemical processes.
This makes theoretical modelling an important tool as a complement to the experimental
techniques.

Chemical processes are characterized by a transition state, a

configuration with the lowest possible (free) energy that links
the product(s) with the reactant(s).

This state is normally not experimentally accessible, but there

are theoretical methods to search for such structures.
Consequently theory is a necessary complement to
experiment.
Chemical reaction in water
movie of water and ethene reacting to form
ethanol. This reaction is acid-catalysed, so the
simulation box contains an hydronium ion
(purple, left of the green ethene molecule). It
donates the blue proton to ethene and
thereby giving it a positive charge. The positive
carbon of ethene attracts the electronegative
oxygen of the other purple water molecule.
When the oxygen attaches to ethene, it loses
one of its protons to another water molecule:
Ethene is transformed into ethanol and the
hydronium ion is recovered.

Ethene Ethanol

http://molsim.chem.uva.nl/gallery/index.html
http://phys.org/news/2013-05-first-ever-high-
resolution-images-molecule-reforms.html
http://phys.org/news/2013-05-first-ever-high-
resolution-images-molecule-reforms.html
Reaction occurs
when T exceeds 90C Product 1

Product 2

http://phys.org/news/2013-05-first-ever-high-
Reactant molecule resolution-images-molecule-reforms.html
 Photoreactions
Theoretical description of photoreactions is particularly challenging: since calculating
electronically excited states is usually more demanding than calculating the ground states
and since the reaction coordinates are often unknown.

Examples study of photoreactions of small, organic molecules (butadiene, cyclohexadiene),

as well as the photoreaction of azobenzene, a molecular rotor and of rhodopsin (the latter in
combination with QM/MM).
The atomic nuclei move (according to the laws of classical mechanics)
in an electronic potential which is calculated using quantum chemical
methods.
Molecular dynamics in the first excited singlet state is performed by means of the ROKS
method (Restricted Open-shell Kohn-Sham)

http://www.theochem.uni-hannover.de/research.html
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Photoreactions
Movie 1 shows the photoreaction of oxirane:
immediately after excitation the C-O bond breaks
in agreement with experimental results,
subsequent hydrogen migration leads to an
aldehyde.

A large amount of the released energy is

transfered to the vibrational degrees of freedom.

Photochemical excitation of diphenyloxirane

leads to cleavage of the C-C bond in a
complicated disrotatory motion, as shown in
movie 2.

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Highly Reactive Mixtures
Movie 3: electron transfer
Hypergolic mixtures are compounds that react spontaneously when brought into contact
with one another. This characteristic is deployed e.g. in the propellant for the upper
stage engine of the European launch vehicle Ariane 5. The bipropellant that is used in
this case consists of monomethylhydrazine (MMH) and nitrogen tetroxide (NTO).
Complications in the upper stage procedure emerged during a mission to transport two
satellites into space in July 2001. A possible reason for this could be undesired reactions
in the bipropellant.

The first electron transfer of a sequence of reaction is shown in movie 3.

http://www.theochem.uni-
hannover.de/research.html 37
Surface Chemistry
The movie shows the reaction of liquid air with aluminium.
The oxygen molecules (red) react readily with the surface while the nitrogen molecules
remain inactive.
The reaction is known as being highly exothermic and a large amount of energy is
released each time an oxygen molecule reacts with the surface. The oxygen molecules
separate into atoms which stick strongly to the surface at an average distance of roughly
4 Angstrom.
Finally also the one water molecule contained in the simulation box reacts with a surface
oxygen atom to yield two hydroxyl groups. At that point, the surface is already close to
melting, as the energy is not removed from the simulation box. While the oxygen atoms
are strongly bonded to the surrounding aluminium atoms, the underlying metal surface
is ductile and allows for some mobility of the surface aluminium oxide islands.

http://www.theochem.uni-
hannover.de/research.html
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Advantages

Calculations are
safe: many experiments have an intrinsic danger associated
with them.
clean: there are no waste chemicals produced.
cost effective: compared to performing experiments.
easy: many experiments can be difficult to perform.
Calculations may also be to give greater insight into the
chemistry by providing more information about the system.

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Disadvantages
Calculations can also be
applied uncritically: just because you can do something
doesnt mean you should.
wrong: there may be approximations in the models used,
or bugs in the code.
a black box: software packages insulate chemists from the
underlying theory.
Computational chemistry is not a replacement for
experimental studies, but plays an important role in enabling
chemists to:
Explain and rationalise known chemistry
Explore new or unknown chemistry

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Conceptual Approach
Validation

Interpretation

Prediction

give us insight, not numbers C. A. Coulson

It is absolutely essential that we know how accurate our

computed results are to be if they are to be of any use: we
want to get the right answer for the right reason.

A celebrated target accuracy is Chemical Accuracy

i.e. to within 1 kcal/mol (~4 kJ/mol) in energy.
A Computational Research Project
What do you want to know? How accurately? Why?
This is your research project
How accurate do you predict the answer will be?
What is an appropriate method to use
How long do you expect it to take?
What method can you feasibly use
What approximations are being made? Which are significant?
Can you actually answer your questions

Once you have finally answered all of these questions, you must
determine what software is available, what it costs and how to
use it.
Assessment
Golden Rule:
Before applying a particular level of theory to an
experimentally unknown situation it is essential to apply the
same level of theory to situations where experimental
information is available

Clearly unless the theory performs satisfactorily in cases where

we know the answer, there is little point in using it to probe
the unknown

Conversely, if the theory does work well in known situations

this lends confidence to the results obtained in the unknown
case.
Flow Chart for a Calculation

Molecule Cartesian
internal
different types for
different purposes
Supplied
Graphically Coordinates
by hand
many different ones:
AMBER, CHARMM,
human input: GROMOS, Sybyl
choice! Program AMPAC, MOPAC,
Difficult VAMP
Gaussian, Gamess,
MOLPRO
Molecular Properties
structures
energies
molecular orbitals
IR, NMR, UV
Interpretation
Overview of Methods
Molecular mechanics, ab initio methods
force fields full quantum method
easy to comprehend only experimental fundamental
quickly programmed constants
extremely fast in principle very high accuracy
no electrons: limited interpretability complete (all interactions are
included)
very time consuming (expensive)
Semiempirical methods
systematic improvement possible
quantum method
valence electrons only
fast Density Functional Theory
limited accuracy quantum method
in principle exact
faster than traditional ab initio
variable accuracy
no systematic improvement
 QUANTUM SCALE
Electronic Structure Methods

Molecule is described by wave function or electron density

To know the properties of these electrons, we probe the wave

function with appropriate operator.

The Schrdinger equation

H E

Ideally the wavefunction would describe the position and momentum

of all atomic nuclei and electrons present.
Obtaining in such a general form is not at all straightforward and so
even in ab initio techniques basic approximations are made. 47