☛ What is FiTMuSiC

FiTMuSiC is a computational tool that, given a protein structure, predicts the impact of all possible single missense variants on its fitness. The FiTMuSiC score is a simple model combining structural and (co)evolutionary protein features.

In the 2022 Critical Assesment of Genome Interpretation (CAGI) blind experiment, FiTMuSiC was one of the best performing methods on the HMBS challenge, in which participants had to predict the impact of 5,593 HMBS variants on its fitness, where we achieved a pearson correlation of 0.42 with the experimental fitness data.

☛ How to submit a query to FiTMuSiC

Running FiTMuSiC is very simple and only requires a protein structure as input. Users can provide either:

• A 4-letter code of a PDB structure, which is then automatically downloaded from the Protein Data Bank.
• A UniProt ID, for which we will download the corresponding AlphaFoldDB structure.
• A personal PDB file (.pdb).

We recommend that users provide protein structures that correspond to biological units because the structure-based features will take into account all the chains contained in the given structure. This is particularly important for homomers and heteromers.

The results of FiTMuSiC will be sent to you by email. Note that depending on the length of your protein, the results could take anywhere between 10 minutes to a few hours. Also note that each user can only run 1 protein at a time.

FiTMuSiC is free to use for academic users only, and thus requires an academic email address. For commercial use or in case of any problem, please contact us.

☛ FiTMuSiC results and interpretation

FiTMuSiC returns a CSV file containing the predicted fitness scores of all single missense variants of the protein. The columns in the CSV include:

1. Columns 1-6: Variant information.
2. Columns 7-8: The residue and the global Multiple Sequence Aligment (MSA) depth.
3. Columns 9-12: Predicted fitness scores, including:
   • FiTMuSiC: The fitness score predicted by FiTMuSiC. The fitness score of the wild type is set to 1, scores close to 0 indicate variants with low fitness, and scores greater than 1 indicate variants with a higher fitness than the wild type.
   • FiTMuSiC_zscore: Normalized FiTMuSiC score.
   • Struct_terms_zscore: Normalized score of the contribution of all the structural terms to the FiTMuSiC score. Negative values indicate that the structural impact of the mutation is releated to a loss of fitness, and vice versa.
   • Evol_terms_zscore: Normalized score of the contribution of all the evolutinonary terms to the FiTMuSiC score. Negative values indicate that the functional effect of the mutations is related to a loss of fitness, and vice versa.

The Z-scores normalize the values to a mean of 0 and standard deviation of 1 with respect to all the protein variants' scores.

The structural and evolutionary Z-scores can be used to interpret whether the variant effect is dominated by structural stability or function.

⦿ Contact

Do not hesitate to contact us at gabriel.cia@ulb.be, matsvei.tsishyn@ulb.be, jean.marc.kwasigroch@ulb.be, marianne.rooman@ulb.be or fabrizio.pucci@ulb.be. Feedback is more than welcome.

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