In silico exploration and molecular dynamics of deleterious SNPs on the human TERF1 protein triggering male infertility

Abstract

By limiting chromosome erosion and end-to-end fusions, telomere integrity is critical for chromosome stability and cell survival. During mitotic cycles or due to environmental stresses, telomeres become progressively shorter and dysfunctional, thus triggering cellular senescence, genomic instability and cell death. To avoid such consequences, the telomerase action, as well as the Shelterin and CST complexes, assure the telomere’s protection. Telomeric repeat binding factor 1 (TERF1), which is one of the primary components of the Shelterin complex, binds directly to the telomere and controls its length and function by regulating the telomerase activity. Several reports about TERF1 gene variations have been associated with different diseases, and some of them have linked these variations to male infertility. Hence, this paper can be advantageous to investigate the association between the missense variants of the TERF1 gene and the susceptibility to male infertility. The stepwise prediction of SNPs pathogenicity followed in this study was based on stability and conservation analysis, post-translational modification, secondary structure, functional interaction prediction, binding energy evaluation and finally molecular dynamic simulation. Prediction matching among the tools revealed that out of 18 SNPs, only four (rs1486407144, rs1259659354, rs1257022048 and rs1320180267) were predicted as the most damaging and highly deleterious SNPs affecting the TERF1 protein and its molecular dynamics when interacting with the TERB1 protein by influencing the function, structural stability, flexibility and compaction of the overall complex. Interestingly, these polymorphisms should be considered during genetic screening so they can be used effectively as genetic biomarkers for male infertility diagnosis.

Communicated by Ramaswamy H. Sarma

Keywords:

• TERF1
• TERB1
• missense variants
• in silico-approach
• male infertility
• molecular dynamic

Authors’ Contributions

HH and HR conceived the idea and designed the objectives. HH and HC carried out the computational study. HH and SR performed the molecular dynamic simulation. HC, OAF and AB participated in the data analysis. HH wrote the paper. All authors read and approved the final manuscript.

Disclosure Statement

The authors declare that they have no conflicts of interest.

Data availability statement

All data are available from the corresponding author upon request.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.