# Decoding the impact of nsSNP variants on BCL6 function through integrated computational analysis

## TL;DR

This study identifies harmful genetic variations in the BCL6 protein that weaken its function and may contribute to lymphoma, using computational methods.

## Contribution

The paper introduces a computational framework to identify and analyze nsSNPs in BCL6 that affect its corepressor interactions and stability.

## Key findings

- Four nsSNPs (Q113K, V105G, I78T, I60T) in BCL6 reduce binding affinity to corepressors.
- MD simulations show mutant BCL6-corepressor complexes are less stable and more flexible.
- These mutations may disrupt BCL6's transcriptional repression and contribute to lymphoma.

## Abstract

BCL6 plays significant roles in various cellular processes and malignancies such as diffuse large B-cell lymphoma. BCL6 performs its functions through binding of its BTB domain to different corepressors. Thus, analyzing the possible structural consequences of nsSNPs on the function of this domain would be imperative. To this end, we have selected the most deleterious SNPs of BCL6 based on various scoring algorithms. Then the selected mutations were modeled, analyzed for various physicochemical and stability properties, and used for molecular docking with the BCoR, NCoR, and SMRT. The obtained complexes were used for the calculation of binding energy and depiction of 2D interaction plots. The docked complexes were also subjected to Molecular Dynamics (MD) simulations to screen their behavior in physiological conditions. The BCL6 SNPs were filtered to 54 nsSNPs of the BTB domain. Using various tools, these nsSNPs were narrowed down to the Q113K, V105G, I78T, and I60T mutations based on their deleteriousness and stability scores. Docking analyses indicated that the exerted mutations mostly reduced the binding affinity, and the MD simulations showed the lower stability of the mutated BCL6 forms during the simulation. Given the attained results, it could be concluded that selected nsSNPs could lead to impaired BCL6 transcriptional repressive function due to loss of stability and binding affinity towards its corepressors. These observations can explain various biological or clinical differences in individuals carrying these SNPs and help with the rational design of novel personalized therapeutics. The results found by computer simulations are suggesting new experiments that need to be done in the future to prove that they are biologically and clinically applicable.

Image 1

•Four deleterious nsSNPs (Q113K, V105G, I78T, I60T) were identified in the BCL6 BTB domain.•These mutations reduce BCL6 binding affinity to corepressors BCoR, NCoR, and SMRT.•MD simulations show increased instability and flexibility in mutant BCL6-corepressor complexes.•Mutations cause slight changes in phosphorylation, glycosylation, and ubiquitination sites.•BCL6 nsSNPs may disrupt transcriptional repression and contribute to lymphomagenesis.

Four deleterious nsSNPs (Q113K, V105G, I78T, I60T) were identified in the BCL6 BTB domain.

These mutations reduce BCL6 binding affinity to corepressors BCoR, NCoR, and SMRT.

MD simulations show increased instability and flexibility in mutant BCL6-corepressor complexes.

Mutations cause slight changes in phosphorylation, glycosylation, and ubiquitination sites.

BCL6 nsSNPs may disrupt transcriptional repression and contribute to lymphomagenesis.