Rchange: algorithms for computing energy changes of RNA secondary structures in response to base mutations

Area of Science:

• Computational Biology
• RNA Structure Analysis
• Bioinformatics

Background:

• Assessing base mutation effects is crucial for RNA functional and evolutionary studies.
• Existing methods for computing thermodynamic changes in RNA secondary structures due to mutations are limited.

Purpose of the Study:

• To develop and present algorithms for systematically calculating thermodynamic changes in RNA secondary structures resulting from single and double base mutations.
• To analyze the impact of mutations on RNA stability and investigate patterns in tRNA sequences.

Main Methods:

• Developed algorithms to compute ensemble free energy, mean energy, and thermodynamic entropy changes for exhaustive single and double mutations.
• Analyzed computational complexities for single (O(NW(2))) and double (O(N(2)W(2))) mutations.
• Investigated 22 tRNA genes in the human mitochondrial genome.

Main Results:

• Calculated thermodynamic changes are largely insensitive to GC composition and maximal base pair span.
• Mean free energy changes are bounded (~7-9 kcal/mol) and weakly position-dependent in long sequences.
• Mutations in the 5' anticodon loop of tRNAs are most stabilizing; acceptor stem mutations are destabilizing.
• Non-pathogenic polymorphisms cause smaller thermodynamic changes than generic mutations in human mitochondrial tRNAs.

Conclusions:

• RNA secondary structure stability is highly optimized, particularly in the acceptor stem.
• Significant alterations in thermodynamic variables due to mutations may indicate pathogenic or lethal effects.
• The Rchange software provides a tool for these thermodynamic analyses.