Molecular modelling

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Molecular Modeling: The Computer is the Lab
Niels Johan Christensen
IGM/Bioinorganic Chemistry/NP3 centre
Overview
• Brief intro to molecular modeling
• Molecular modeling at the NP3 centre: Application to novel insulin
complexes
• Clustering
• Acknowledgements
• Questions
Slide 2
What is Molecular Modeling?
Wikipedia´(http://en.wikipedia.org/wiki/Molecular_modelling):
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
treatment
•Highly flexible – any property can in
principle be calculated
Typical applications
 Simulating biomolecules in explicit
solvent/membrane
 Geometry optimization
 Conformational search
Slide 4
 Chemical reactions
 Spectra
 Accurate (gas phase) structures,
energies
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)
*http://www.np3.life.ku.dk/
Prelude: Isomers of a (2,2’)-bipyridine Fe(II) complex
Meridional (mer) Facial (fac)

-fac
-mer
Slide 6

 -fac
 -mer
Circular dichroism
• Measures differential absorption of left and right circularly polarized light by chiral
molecules
• Only CD can establish the absolute configuration of molecules in solution
Slide 7
Image source: http://en.wikipedia.org/wiki/Circular_dichroism
Engineered insulin as a building block in bionanotechnology
Hexamer of native insulin. Zinc (grey
sphere) coordinated by HisB10 (green
licorice)
Monomers of engineered insulin:
Bipyridine has been introduced at position
A1 (left) or B29 (right). HisB10 is also
shown
Slide 8
Insulin chain figure from : http://www.abpischools.org.uk/page/modules/diabetes_16plus/diabetes5.cfm?coSiteNavigation_allTopic=1
Three bipy-functionalized insulins form 4 distinct complexes with
iron(II). Here, B29 functionalized insulin (similar for A1):
[Fe(
 -fac
-fac
2+
)3]
-mer
Which species dominate in solution?
Slide 9
-mer
Circular Dichroism – calculated vs measured
B29
Measured
Calculated
Slide 10
-fac
Erel(QM) = 0.0 kJ/mol
A1
Measured
B29
Calculated
-fac
Erel(QM) = 0.0kJ/mol
-mer
Erel(QM) = 2.1 kJ/mol
Calculated
Calculated
QM calculations on truncated systems (inset), measurements on B29 and A1
engineered insulin trimers in solution with Fe(II)
-mer
Erel(QM) = 2.1 kJ/mol
A1
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
-fac
14.3 kJ/mol
-mer
25.4 kJ/mol
-mer
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
Acknowledgements
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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