smturzo / mochi

Neural networks to quantify energies, energetic couplings, epistasis and allostery from deep mutational scanning data

MoCHI

Welcome to the GitHub repository for MoCHI: Neural networks to quantify energies, energetic couplings, epistasis and allostery from deep mutational scanning data.

Table Of Contents

1. Installation
2. Usage
   1. Option A: MoCHI command line tool
   2. Option B: Custom python script
   3. Demo
3. Manual
4. Bugs and feedback
5. Citing MoCHI

Installation

The easiest way to install MoCHI is by using the bioconda package:

conda install -c bioconda pymochi

See the full Installation Instructions for further details and alternative installation options.

Usage

You can run a standard MoCHI workflow using the command line tool or a custom analysis by taking advantage of the "pymochi" package in your own python script.

MoCHI requires a table describing the measured phenotypes and how they relate to the underlying additive (biophysical) traits. The table should have the following 4 columns (see example file here):

• trait: One or more additive trait names
• transformation: The shape of the global epistatic trend (Linear/ReLU/SiLU/Sigmoid/SumOfSigmoids/TwoStateFractionFolded/ThreeStateFractionBound)
• phenotype: A unique phenotype name e.g. Abundance, Binding or Kinase Activity
• file: Path to DiMSum output (.RData) or plain text file with variant fitness and error estimates for the corresponding phenotype

Option A: MoCHI command line tool

$ conda activate pymochi
$ run_mochi.py --model_design model_design.txt

Get help with additional command line parameters:

$ run_mochi.py -h

Option B: Custom python script

Below is an example of a custom MoCHI workflow to infer the underlying free energies of folding and binding from doubledeepPCA data.

1. Create a MochiTask object with one-hot encoded variant sequences, interaction terms and 10 cross-validation groups:

   import pymochi
   from pymochi.data import MochiData
   from pymochi.models import MochiTask
   from pymochi.report import MochiReport
   import pandas as pd
   
   k_folds = 10
   
   my_model_design = pd.DataFrame({
      'phenotype': ['Abundance', 'Binding'],
      'transformation': ['TwoStateFractionFolded', 'ThreeStateFractionBound'],
      'trait': [['Folding'], ['Folding', 'Binding']],
      'file': ["dimsum_abundance_fitness.RData", "dimsum_binding_fitness.RData"]})
   
   mochi_task = MochiTask(
      directory = 'my_task',
      data = MochiData(
         model_design = my_model_design,
         max_interaction_order = 1,
         k_folds = k_folds))
   

2. Hyperparameter tuning and model fitting:

   mochi_task.grid_search() 
   
   for i in range(k_folds):
      mochi_task.fit_best(fold = i+1)
   

3. Generate MochiReport, phenotype predictions, inferred additive trait summaries and save task:

   temperature = 30
   
   mochi_report = MochiReport(
      task = mochi_task,
      RT = (273+temperature)*0.001987)
   
   energies = mochi_task.get_additive_trait_weights(
      RT = (273+temperature)*0.001987)
    
   mochi_task.save()
   

   Load previously saved task:

   mochi_task = MochiTask(directory = 'my_task')
   

Report plots, predictions and additive trait summaries will be saved to the "my_task/report", "my_task/predictions" and "my_task/weights" subfolders.

Demo MoCHI

Run the demo to ensure that you have a working MoCHI installation (expected run time <10min):

$ demo_mochi.py

Manual

Comprehensive documentation is coming soon, but in the meantime get more information about specific classes/methods in python e.g.

help(MochiData)

Bugs and feedback

You may submit a bug report here on GitHub as an issue or you could send an email to [email protected].

Citing MoCHI

Please cite the following publications if you use MoCHI:

Faure, A. J., Domingo, J., Schmiedel, J. M., Hidalgo-Carcedo, C., Diss, G., & Lehner, B. Mapping the energetic and allosteric landscapes of protein binding domains. Nature, 604(7904), 175–183 (2022). 10.1038/s41586-022-04586-4

Weng, C., Faure, A. J., & Ben Lehner. The energetic and allosteric landscape for KRAS inhibition. bioRxiv, 2022.12.06.519122 (2022). 10.1101/2022.12.06.519122

Acknowledgements

Project based on the Computational Molecular Science Python Cookiecutter version 1.6.

(Vector illustration credit: Vecteezy!)