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Molecular Modeling: The Computer is the LabNiels Johan ChristensenIGM/Bioinorganic Chemistry/NP3 centre
Slide 2
Overview
• Brief intro to molecular modeling
• Molecular modeling at the NP3 centre: Application to novel insulin complexes
• Clustering
• Acknowledgements
• Questions
Slide 3
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….
Wikipedia´(http://en.wikipedia.org/wiki/Molecular_modelling):
…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.
Andrew R. Leach, ”Molecular modelling, principles and applications”, second edition:
Slide 4
The Molecular Modeling Toolbox
Molecular Mechanics Methods
Molecules modeled as spheres (atoms) connected by springs (bonds)
• Fast, >106 atoms
• Limited flexibility due to lack of electron treatment
Quantum Mechanical Methods
Molecules represented using electron structure (Schrödinger equation)
• Computationally expensive , <10-100 atoms, depending on method
•Highly flexible – any property can in principle be calculated
Typical applications Chemical reactions
Spectra
Accurate (gas phase) structures, energies
Simulating biomolecules in explicit solvent/membrane
Geometry optimization
Conformational search
Slide 5
The insulin project at the NP3 centre*
• Synthesis: Engineered insulin with a novel metalion binding-site
• Experimental data: CD, UV-vis
• Goal: Elucidate the structure of a the novel insulin-complex in solution
• Molecular modeling methodologies employed:
• Molecular mechanics
• Molecular dynamics
• Quantum mechanics (Density functional theory)
*http://www.np3.life.ku.dk/
Slide 6
Prelude: Isomers of a (2,2’)-bipyridine Fe(II) complex
-fac
-mer
-fac
-mer
M
eri
dio
nal (m
er)
Faci
al (f
ac)
Slide 7
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
Image source: http://en.wikipedia.org/wiki/Circular_dichroism
Slide 8
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
Insulin chain figure from : http://www.abpischools.org.uk/page/modules/diabetes_16plus/diabetes5.cfm?coSiteNavigation_allTopic=1
Slide 9
Three bipy-functionalized insulins form 4 distinct complexes with iron(II). Here, B29 functionalized insulin (similar for A1):
-fac -fac -mer
[Fe( )3]2+
-mer
Which species dominate in solution?
Slide 10
Circular Dichroism – calculated vs measured
-facErel(QM) = 0.0kJ/mol
-fac Erel(QM) = 0.0 kJ/mol
-merErel(QM) = 2.1 kJ/mol
-merErel(QM) = 2.1 kJ/mol
Calc
ula
ted
Calc
ula
ted
Measu
red
Calc
ula
ted
Measu
red
Calc
ula
ted
B29 B29 A1 A1
QM calculations on truncated systems (inset), measurements on B29 and A1 engineered insulin trimers in solution with Fe(II)
Slide 11
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 12
Conformational search on a truncated B29 trimer
-fac0.0 kJ/mol
-fac14.3 kJ/mol
-mer25.4 kJ/mol
-mer30.0 kJ/mol
Conformational search: [Fe(bipy)3]2+ core fixed, rotate remaining groups systematically to find lowest energy:
Slide 13
Molecular dynamics simulations can be used to elucidate the dynamics of biomolecules
• Example: Rearrangement of an engineered insulin monomer
Slide 14
Clustering: Building a larger calculator
Slide 15
Acknowledgements
Det Strategiske Forskningsråds Programkomite for Nanovidenskab og -teknologi, Bioteknologi og IT (NABIIT)
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, Denmarkb Bioorganic Chemistry, Department of Basic Sciences and Environment, Faculty of Life Sciences, University of Copenhagen, Denmarkc Novo Nordisk , Maaloev, Denmark