Impact of non-synonymous mutations on the structure and function of telomeric repeat binding factor 1

Area of Science:

• Genetics and Molecular Biology
• Structural Biology
• Computational Biology

Background:

• Telomeric repeat binding factor 1 (TRF1) is crucial for telomere maintenance and is part of the shelterin complex.
• Variations in the TRF1 gene are linked to various diseases, highlighting the need to understand their functional impact.

Purpose of the Study:

• To investigate the structural and functional significance of variations within the TRFH domain of TRF1.
• To identify deleterious mutations in TRF1 and analyze their impact on protein structure and stability.

Main Methods:

• Utilized multiple computational tools (SIFT, PolyPhen-2, PROVEAN, Mutation Assessor, mCSM, SDM, STRUM, MAESTRO, DUET) to predict the effects of 124 TRF1 mutations.
• Performed 200 ns all-atom molecular dynamics (MD) simulations on wild-type TRF1 and selected mutants (L79R, P150R).

Main Results:

• Identified 12 high-confidence deleterious mutations within the TRF1 TRFH domain.
• Observed significant conformational changes in the P150R mutant structure through MD simulations, indicating altered protein stability and function.

Conclusions:

• This integrated computational approach provides insights into how TRF1 mutations affect its structure and function.
• Understanding these mutation-induced structural changes is vital for comprehending disease progression associated with TRF1 variations.