Molecular modelling

Molecular Modeling: The Computer is the Lab
Niels Johan Christensen
IGM/Bioinorganic Chemistry/NP3 centre
• Brief intro to molecular modeling
• Molecular modeling at the NP3 centre: Application to novel insulin
• Clustering
• Acknowledgements
• Questions
Slide 2
What is Molecular Modeling?
Molecular modelling encompasses all theoretical methods and computational techniques used to model or mimic
the behaviour of molecules. The techniques are used in the fields of computational chemistry, computational biology
and materials science for studying molecular systems ranging from small chemical systems to large biological
molecules and material assemblies…. inevitably computers are required to perform molecular modelling of any
reasonably sized system….
Andrew R. Leach, ”Molecular modelling, principles and
applications”, second edition:
…we shall not concern ourselves with semantics but rather shall consider any theoretical or computational
technique that provides insight into the behaviour of molecular systems to be an example of molecular modelling.
Slide 3
The Molecular Modeling Toolbox
Molecular Mechanics Methods
Quantum Mechanical Methods
Molecules modeled as spheres (atoms)
connected by springs (bonds)
Molecules represented using electron
structure (Schrödinger equation)
• Fast, >106 atoms
• Computationally expensive , <10-100
atoms, depending on method
• Limited flexibility due to lack of electron
•Highly flexible – any property can in
principle be calculated
Typical applications
 Simulating biomolecules in explicit
 Geometry optimization
 Conformational search
Slide 4
 Chemical reactions
 Spectra
 Accurate (gas phase) structures,
The insulin project at the NP3 centre*
Synthesis: Engineered insulin with a novel metalion bindingsite
Experimental data: CD, UV-vis
Goal: Elucidate the structure of a the novel insulin-complex
in solution
Molecular modeling methodologies employed:
Slide 5
Molecular mechanics
Molecular dynamics
Quantum mechanics (Density functional theory)
Prelude: Isomers of a (2,2’)-bipyridine Fe(II) complex
Meridional (mer) Facial (fac)
Slide 6
 -fac
 -mer
Circular dichroism
• Measures differential absorption of left and right circularly polarized light by chiral
• Only CD can establish the absolute configuration of molecules in solution
Slide 7
Image source:
Engineered insulin as a building block in bionanotechnology
Hexamer of native insulin. Zinc (grey
sphere) coordinated by HisB10 (green
Monomers of engineered insulin:
Bipyridine has been introduced at position
A1 (left) or B29 (right). HisB10 is also
Slide 8
Insulin chain figure from :
Three bipy-functionalized insulins form 4 distinct complexes with
iron(II). Here, B29 functionalized insulin (similar for A1):
 -fac
Which species dominate in solution?
Slide 9
Circular Dichroism – calculated vs measured
Slide 10
Erel(QM) = 0.0 kJ/mol
Erel(QM) = 0.0kJ/mol
Erel(QM) = 2.1 kJ/mol
QM calculations on truncated systems (inset), measurements on B29 and A1
engineered insulin trimers in solution with Fe(II)
Erel(QM) = 2.1 kJ/mol
Circular Dichroism – calculated vs measured
• Comparison of measured/calculated CD sign changes
allows determination of enantiomer dominating in
solution: A1 (), B29 ()
• Meridional (mer) and facial (fac) configuation cannot
be firmly established from CD alone.
• Energies from a conformational search on (truncated)
systems may help in determining fac/mer preferences
Slide 11
Conformational search on a truncated B29 trimer
Conformational search: [Fe(bipy)3]2+ core fixed, rotate remaining
groups systematically to find lowest energy:
 -fac
0.0 kJ/mol
Slide 12
14.3 kJ/mol
25.4 kJ/mol
30.0 kJ/mol
Molecular dynamics simulations can be used to elucidate the
dynamics of biomolecules
Example: Rearrangement of an engineered insulin monomer
Slide 13
Clustering: Building a larger calculator
Slide 14
Henrik K. Munchb, Søren Thiis Heidea, Thomas Hoeg-Jensenc, Peter
Waaben Thulstrupa and Knud J. Jensenb
a Bioinorganic
Chemistry, Department of Basic Sciences and Environment, Faculty of Life Sciences, University of
Copenhagen, Denmark
b Bioorganic Chemistry, Department of Basic Sciences and Environment, Faculty of Life Sciences, University of
Copenhagen, Denmark
c Novo Nordisk , Maaloev, Denmark
Det Strategiske Forskningsråds Programkomite for Nanovidenskab og -teknologi,
Bioteknologi og IT (NABIIT)
Slide 15
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