# Fragmenstein — full merger

> This documenation may be out of date.

* First the inspiration hits are merged regardless of horrid torsions and bond lengths via one of three modes
* Then the followup compound is mapped on (with appropriate atom changes) and novel parts added
* Then the compound is minimised in the protein with constraints to the mapped atoms.


* `.scaffold` is the combined version of the hits (rdkit.Chem.Mol object).
* `.chimera` is the combined version of the hits, but with differing atoms made to match the followup (rdkit.Chem.Mol object).
* `.positioned_mol` is the desired output (rdkit.Chem.Mol object)

Note, the hits have to be in the same coordinate reference system —i.e. extracted from crystal structures in bond form.

`.get_positional_mapping`, which works also as a class method, creates a dictionary of mol_A atom index to mol_B atom index
based on distance (cutoff 2Å) and not MCS.

The code works in two broad steps, first a scaffold is made, which is the combination of the hits (by position).
Then the followup is placed. It is not embedded with constraint embed, which requires the reference molecule to have a valid geometry.
`.scaffold` and `.chimera` and `.positioned_mol` absolutely do not have this.
Novel side chains are added by superposing an optimised conformer against the closest 3-4 reference atoms.
Note that `.initial_mol` is not touched. `.positioned_mol` may have lost some custom properties, but the atom idices are the same.

## Algorithm

The following steps are done:

* `.simply_merge_hits()`: merges the hits, the output `rdkit.Chem.Mol` object added as `.scaffold`.
* `.make_chimera()`: makes the atomic elements in `.scaffold` match those in the followup, the output `rdkit.Chem.Mol` object added as `.chimera`.
* `.place_from_map()`  followup is places like the scaffold.

## Merger
The merger of the hits does not use MCS.
Instead all atoms are matched uniquely based on cartesian position with a cutoff of 2 Å (changeable).
The method ``get_positional_mapping`` works as a class method, so can be used for other stuff.
Here are the atoms in x0692 that map to x0305 and vice versa.

<img href="image0.svg" alt="x0692 common with x0305" width="200px">
<img href="image1.svg" alt="x0305 common with x0692" width="200px">

With maximum common substructure, a benzene ring can be mapped 6-ways, here none of that ambiguity is present although different issues arise.
Then the next step is fragment the second molecule to get the bits to add.

<img href="image2.svg" alt="fragments of x0305" width="200px">
<img href="image3.svg" alt="fragments of x0305" width="200px">
<img href="image6.svg" alt="fragments of x0305" width="200px">

The first fragment when added results in:

<img href="image3.svg" alt="fragments of x0305" width="200px">
<img href="image4.svg" alt="fragments of x0305" width="200px">
<img href="image5.svg" alt="fragments of x0305" width="200px">

Ditto for the second:

<img href="image8.svg" alt="fragments of x0305" width="200px">

And ditto again for a second fragment (x1249):

<img href="image14.svg" alt="fragments of x0305" width="200px">

## Elemental changes

During the elemental change, valence is taken into account resulting in appropriate positive charge.
This step is needed to avoid weird matches with the followup.

## Example

    hits = [Chem.MolFromMolFile(f'../Mpro/Mpro-{i}_0/Mpro-{i}_0.mol') for i in ('x0692', 'x0305', 'x1249')]
    followup = Chem.MolFromSmiles('CCNc1nc(CCS)c(C#N)cc1CN1C(CCS)CN(C(C)=O)CC1')
    monster = Fragmenstein(followup, hits)
    #monster = Fragmenstein(followup, hits, draw=True) for verbosity in a Jupyter notebook
    monster.make_pse('test.pse')
    
    display(monster.scaffold)
    display(monster.chimera) # merger of hits but with atoms made to match the to-be-aligned mol
    display(monster.positioned_mol) # followup aligned
    
    # further alignments... not correct way of tho
    monster.initial_mol = new_mol
    aligned = monster.place_from_map(new_mol)

    
## Issues to be aware of

> See also [work in progress](wip.html)

Here is an example with a few issues.

<img href="unconnected.jpg" alt="unconnected" width="400px">

### Non-overlapping fragments

Non-overlapping fragments are discarded. Ideally they should be joined using the followup compound as a template _if possible_.
In the pictured case the SMILES submitted may not have been what was intended and should not be used connect the fragments.

### More than 4 templates

<img href="v_ugly.jpg" alt="ugly" width="400px">

When there are too many templates with large spread, these aren't merged resulting in a spiderweb scaffold.
This results in a non-unique mapping.