http://pistoiaalliance.org @PistoiaAlliance

Pistoia Alliance HELM

Project - What About the Big

Guys?The emerging HELM standard for macromolecular representation

Domain Lead – Sergio RotsteinBusiness Technology, Pfizer

What is a “Biomolecule”?

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Peptides

Therapeutic Proteins

ADCs

Antibodies

Vaccines

ASOs

siRNAs

For our purposes, anything that is not a small molecule is a biomolecule

Goal

• Eliminate biomolecule penalty

• Make these entities first-class citizens of the Informatics tool portfolio

GAP

So what’s the problem?

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N

NH

O

O

O

N

NH

O

O

O

Small Molecules

Sequences

Biomolecules

Small Molecule Tools Sequence-Based Tools

“Fit-for-Purpose” Structure Representation

We need to enable the representation, manipulation and visualization of each molecule type in a way that is appropriate for its size and complexity

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Fit for Purpose: “Monomer” Level• While you could draw out an oligonucleotide like

this:

• The representation is likely more intuitive / practical:

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Fit for Purpose: Sequence Level

• But even the monomer level representation would not scale well to proteins with hundreds of amino acids. Larger molecules require a more sequence-oriented representation:

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Fit for Purpose: Component Level

• For multi-component structures such as antibody drug conjugates, component level representations are required to enable each component to dealt with separately.

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F

O

OO

O N

N

“Collapsed” Antibody

Expanded Drug

Ab

Hierarchical Editing Language for Macromolecules

– Hierarchical – Amenable to the various “levels”• Complex Polymer ⇒ Simple Polymer ⇒ Monomer ⇒

Atom– Extensible

• Allowing addition of new biopolymer types– (Reasonably) comprehensive

• e.g. Allowing representation of oligonucleotide hybridization

– Canonicalizable• Facilitating uniqueness checking

– (Somewhat) human-readable

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HELM Example: Simple polymer

• HELM notation: A.R.G.[dF].C.K.[ahA].E.D.A

– Non-natural amino acid codes are enclosed in square brackets

• Natural equivalent: ARGFCKXEDA9

HELM Example: Complex Polymer

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Monomer Database

• Each monomer used in the notation needs to be predefined in a monomer database

• The database includes the chemical structure of the monomer and a description of all acceptable attachment points

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J. Chem. Inf. Model 2012, 52, 2796-2806

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