Meeting Noel Carrascal on molecular modelling

Hi all, yesterday (2nd of June) I had a Google Hangout with Noel Carrascal on designing the insulin construct. Relevant to @WinniePoncelet, @BramDeJaegher.

Post-translational insulin consists of two chains (A and B) that are bonded through disulfide bonds. In humans this is obtained through post-translational modification of a single peptide chain. Such machinery is not available in an E. coli host. Noel is studying how to design the construct for insulin such that a the two parts can reliably find each other.

His design is based on the strong affinity between barnase and barstar. Barnase (resp. barstar) are connected to one of the insulin chains using a linker. When the barnase-barstar complex is formed, insulin should form by proximity. This also circumvents the risk of the formation of two chains of the same kind bonding (A-A or B-B).

Such insuline-barnase-barnstar complexes should aggregate into a large complex of many such molecules, from which pure, functional insulin can easily be cleaved. Admittedly, I did not follow this 100%.

The challenge here is to design such linker as such the complex can be formed. To this end, Noel writes his own software to do mechanistic molecular modelling. He computes all the molecular (polar, Vanderwaals, …) interactions between amino acids to finally obtain the stability of a complex. For a given linker, this is represented by a set of (sparse) matrixes quantifying the strength of the interactions between the amino acids.

This is the point where machine learning comes into play:

  • Using a set of example matrices, predict the matrices for new AA chains
  • Perhaps use the information to directly build a model to predict stability of a given linker? The mechanistic information should somehow be used to improve the model (i.e. Vapnik’s learning with privileged information)
  • Given a model, optimize the linker (SA, GA…)
  • Bayesian optimization to search for promising under model uncertainty?

Michiel out!

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Did I understand?

Hi @Michielstock , good to read you had the call with Noel.

Let me rephrase this to see if I understood correctly: your work with machine learning uses the output of Noel’s computational work (matrices) as input, and when you have sufficient data, you can ‘shortcut’ the work by using those matrices directly to generate new matrices. In essence, automating, optimising and speeding up the modelling that he does now. Am I in the ball park?

Did you make any plans for what’s next?

PS tagging someone fails sometimes when there is no space behind the tag. Like this it works @BramDeJaegher .