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