Functional implications of SNPs in spliceosomal network: a structural systems biology approach

Area of Science:

• Molecular Biology
• Structural Biology
• Systems Biology

Background:

• The spliceosome is crucial for messenger RNA splicing.
• Single Nucleotide Polymorphisms (SNPs) in spliceosomal proteins are linked to diseases.
• Structural and mutational data offer insights into spliceosome function.

Purpose of the Study:

• To investigate the functional consequences of SNPs in spliceosomal proteins using integrated sequence and structure-based methods.
• To develop a structural systems biology framework for analyzing SNP impacts on spliceosome function.

Main Methods:

• Calculated changes in binding free energy (ΔΔG) for SNPs and compared them to known mutations.
• Utilized homologous protein structures and multiple-sequence alignment for variants when human structures were unavailable.
• Employed FoldX for ΔΔG estimation, visualized protein-protein interactions, and used molecular dynamics (MD) simulations for structural analysis.
• Mapped variants onto yeast spliceosome complexes to evaluate stage-specific effects.

Main Results:

• ΔΔG values for SNPs were comparable to experimentally determined mutations.
• Protein-protein interaction networks revealed potential functional impacts of SNPs.
• MD simulations assessed SNP-induced structural perturbations.
• Analysis of the U2AF35-U2AF65 complex showed comparable ΔΔG values across different modeling approaches, though interface variations were noted.

Conclusions:

• The study establishes a structural systems biology approach to understand how SNPs affect spliceosome function and splicing.
• This framework aids in evaluating the impact of genetic variations on splicing and associated diseases.
• Further research is needed to refine models and interpret findings cautiously, especially concerning complex interactions and large spliceosome size.