Cheminformatics & Validation
Molecular modelling
 Introduction
 Molecular mechanics/dynamics
– Conformational analysis

Electronic structure methods
– Transition states

Density functional theory
– Crystalline state
1
25-Feb (JS)
26-Feb (NG)
27, 4 & 6th Feb/March
13-Mar (JS)
18th & 20th Mar
26-Mar (PM)
27th Mar & 1 & 3 Apr
Introduction to molecular modelling
Predicting properties of molecules, such as energy,
structure, polarisability, dipole moment, etc.
including reaction profiles and transition states
 Focus on the application Spartan
 Practical sessions: Monday afternoons 2am

– Feb: 17 & 24 (NG)
– Mar: 3 & 10 (JS)
17, 24 (PM)
– Location: Corrib suite

2
Registration, usernames, passwords, etc.
Informatics (normally Wed 9am)

World wide web (JS)
– Tue March 25th

Chemical Abstracts via STN (LS)
– 12th & 19th March

Beilstein CrossFire (NG)
– 11th March

Cambridge crystallography database (PM)
– 26th March & 2nd April
3
Comparisons at a glance
4
Molecular mechanics: Introduction

Molecular mechanics (each different force field)
– eg AMBER, OPLS, BIO+, MM+
Potential energy of molecule location of atoms
 Atom types? Just elements?

– eg 5 different oxygens
– carbonyl, hydroxyl, carboxylic, ester or water
Parameter sets; elements parametrised
 Interaction of nuclei not electrons

5
Force fields
6
ES = (k/2) (r - r0)2

Bond str.:

Angle bending: EB = kq (q- q0)2

Torsion:

van der Waals: ENB = AIJ r -12 - BIJ r -6

Electrostatic:

H-bonding: 10-12 potential
Ew = VN{1+cos (nf -f0)}/2
EE = qI qJ/(er)
Applications
7

Geometry optimisation

Molecules with 1,000s of atoms

Organics, oligonucleotides, peptides, etc.

Metallo-organics and inorganics

Vacuum and solvent

Ground states only
Electronic structure methods

ab initio: purely theoretical
– many different approximations
– Hartree-Fock, e correlation: MPn, MCSCF
– basis sets: STO-3G, 6-31G(d), 6-311+G(d,p), etc

Semi-empirical: some exptal. data
– many different expressions: MNDO, AM1, PM3

Density functional theory (ab initio?)
– many different
– B3LYP, SVWN, etc
8
Semi-empirical methods
Very large systems & 1st step for large systems
 Ground state organic molecules

– Calibration: parametrised
– AM1: H, B/Al, C/Si/Ge, N/P, O/S, F/Cl/Br, Zn
Energies
 Geometry optimisation
 Frequencies


9
Molecular orbitals (!?)
E = f(x)
dE/dx
d2E/dx2
Example
2
X
OH
3
Bredt’s rule:
 “Elimination to give a double bond in a bridged
bicyclic system always leads away from the
bridgehead”
 Build #2 and #3 optimise and record the energy;
which is more stable?
 Why? Measure C=C bond lengths (130-132 pm)
Effect of increasing ring size?
10
Practical: acetone


Build, minimise & optimise via AM1 (H3C)2CO
Experimental data:
– Heat of formation DHF = -51.9 kcal/mol
– Dipole moment = 2.88 Debyes

Energy levels and MOs
– Identify HOMO
– View HOMO & LUMO (Setup/Surfaces/Add/HOMO then up to
Setup/Submit)

Vibrational analysis
– Identify vibrations and IR spectrum
– C=O stretching vibration?
11
Structure versus Energy

Hexasilabenzene can exist in several
isomeric forms; Sax et al. [J. Comp.
Chem. 1988, 9:564–77] found that
the prismane, isomer 2, is the most
stable, do you agree (AM1)?
H
H
Si Si Si H
Si Si Si
H
H
12
H
H
H
Si
Si
Si
Si
Si
Si
H
H
H
H
H
H Si
Si H
Si
H Si Si Si
H
H
Si
H
Si
Si
H Si
Si H
Si
H
H
Exercise: Walsh Diagrams


13
Walsh diagrams are useful in predicting molecular
geometry. They correlate energy changes of molecular
orbitals between a reference geometry, frequently of high
symmetry, and a deformed structure of lower symmetry.
Sketch the water molecule, aligning it on screen; set a
restraint or constraint (by clicking on ‘angle padlock’ icon)
select the H–O–H angle so that the angle is forced to be
say 90º. Do a geometry optimisation with AM1.
Example: geometry optimisation

Malonaldehyde
– Simple example of
intramolecular H-bonding
124.5°
– Cf. experimental structure
with a geometry optimisation run
1.089 H
– Try molecular mechanics &
– Semi-empirical, PM3
– Key distance: long O...H
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1.091
H
1.348
1.454
1.32 119.4°
1.234
O
O
0.969 H
1.68
123°
H
1.094
The log file



Orientation of molecule
Mulliken population
analysis partitions total
charge among the atoms
of the molecule (widely
used & criticized)
Dipole moment of 1.709
– y-component of 1.709
– So points from negative O
atom along Y-axis
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Y
H
H
O
X
Portion of log file
Eigenvalues(a.u.) and Eigenvectors
Mol. Orbital
1
2
3
4
5
Eigenvalue -20.25158 -1.25755 -0.59385 -0.45973 -0.39262
S O
1
0.99422
0.23377 0.00001 -0.10404 0.00000
S O
1
0.02585 -0.84445 -0.00004 0.53817 0.00000
Px O
1
0.00000
0.00000 -0.61270 -0.00008 0.00000
Py O
1
0.00416 -0.12284 0.00008 -0.75587 0.00000
Pz O
1
0.00000
0.00000 0.00000 0.00000 1.00000
S H
2
-0.00558 -0.15559 -0.44922 -0.29512 0.00000
S H
3
-0.00558 -0.15560 0.44923 -0.29509 0.00000
EIGENVALUES(eV)
-551.073608 -34.219627 -16.159496 -12.509945 -10.683656
NET CHARGES AND COORDINATES
Atom Z
Charge
Coordinates(Angstrom)
(Mulliken)
x
y
z
1
8 -0.330524
-0.00000774 -0.07115177 0.00000000
2
1
0.165255
0.75813931
0.56460971 -0.00000005
3
1
0.165271
-0.75801641
0.56471276 0.00000005
16
6
0.58179
7
0.69267
0.12582 0.00003
-0.82013 -0.00019
-0.00024 0.95980
-0.76356 -0.00023
0.00000 0.00000
0.76930 -0.81449
0.76902 0.81480
15.831361 18.848427
Mass
15.99900
1.00800
1.00800
Open versus closed shell
How to handle electron spin

Open shell (unrestricted)  4
– odd no. of e’s
– excited states
– 2 or more unpaired e’s
– bond dissociation

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Closed shell (restricted)


4
3
3
2
2


1
1
Relative Computation Times
Methylcyclohexane (7 heavy atoms)
Lysergic acid (20)
Energy
(Single-point)
0.01
Geometry
Optimisation
Frequency
0.08
0.66
HF 3-21G
1
14
190
HF 6-31G*
AM1
5.4
0.05
90
1.9
1100
11
3-21G
17
600
6-31G*
120
AM1
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Transition states
Finding TSs (more difficult than minima)
 Mathematical procedures less well developed
 PE surface near TS probably “flatter”
 Only good ab initio methods will work

– bonds partially or fully broken
Very little quantitative data on TSs anyway
 Guessing TSs

– Closely-related system
– Average reactant & product (linear synchronous transit)
– Chemical intuition
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Verifying TS
Frequency normal-mode analysis
 One (and one only) imaginary frequency

– eg a negative frequency in the range 400-2,000 cm-1

Check that the coordinate (corresponding to
imaginary frequency) smoothly connects reactants
and products by:
– coordinate animation
– follow the coordinate by intrinsic reaction coordinate
methods
20
Pyrolysis of ethyl formate
H
O

H
O
H
H
+
H
H
H
O
O
H
Build ethyl formate, choosing the correct geometry, minimise
with AM1, save one copy as
– Ethyl_formate_pBP_DNss
for later & another as
– Ethyl_formate_pyrolysis_AM1 for use now.


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Select Reaction from Build menu (or curved arrow icon); click
on bond ‘a’ then on ‘b’; then on ‘c’ & ‘d’ and finally on ‘e’
followed by Shift click on methyl H to be transferred and on the
O-atom to receive it.
With all three arrows in place, click on equilibrium icon (twin
arrows) at the bottom right of screen
Transition state of ethyl formate






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Result; shown on the right
Enter Calculations dialogue, specify
TS geometry, semi-empirical & AM1
Click on frequencies
Submit job, when finished examine
geometry & animate imaginary (-ve)
frequency
Is vibrational motion consistent with
reaction?
Turn off animation by re-entering
Vibrations & clicking on imaginary
frequency.
eH
d
O
a
c O b H
Density iso-surface





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Bring up Surfaces dialogue,
click on Add … select density
(bond) & none from Property
menu & click on OK. Repeat
with potential from Property.
Submit.
Enter Surfaces & click on
density completed 0.08
Is CO bond in ethyl formate
nearly fully cleaved?
Is the migrating H midway
between C & O?




Click anywhere on graphic,
select either Transparent or
Mesh from the menu to the right
of Style (bottom right) to replace
opaque solid density surface by
a mesh or transparent solid view
Click on density Completed 0.08
then click again
Check migrating H colour code
Is it ?
– H+ (blue)
– H (green) or
– H– (red)
Computation of activation energy




Use “ethyl_formate_pBP_DNss”
Enter Calculations dialogue, specify single-point using the
pBP/DN** DFT model, click OK & submit job.
Bring on-screen “ethyl_formate_pBP_DNss”.
Enter Calculations, specify pBP/DN** but start from an AM1
structure. Submit job
When both calculations are complete, compute the activation
energy from the difference between the total energies of TS and
ethyl formate (use molecular properties from the Display menu)
1 atomic unit (au) = 627.51 kcal/mol

24
How does your value cf. with exptal. of 40-44 kcal/mol?