mRNA/protein sequence complementarity and its determinants: The impact of affinity scales

Area of Science:

• Molecular Biology
• Bioinformatics
• Biophysics

Background:

• mRNA and protein sequences show complementary nucleobase-density and affinity profiles.
• This suggests potential co-aligned binding between mRNA and cognate proteins, particularly in unstructured regions.

Purpose of the Study:

• To investigate how mRNA/protein sequence complementarity depends on the specific nucleobase/amino-acid affinity scales used.
• To explore the characteristics of optimized and suboptimal affinity scales for mRNA-protein interactions.

Main Methods:

• Employed a Monte Carlo strategy to sample random nucleobase/amino-acid affinity scales.
• Utilized a fitness function based on sequence complementarity to guide scale optimization.
• Analyzed scales across model organisms from all three domains of life.

Main Results:

• Searches consistently converged on highly optimized affinity scales, indicating a funnel-like fitness landscape.
• Optimized scales, derived without physicochemical considerations, closely mirrored experimentally determined RNA-protein binding affinity scales.
• Suboptimal scales revealed that diverse scales can achieve significant complementarity, with specific amino acids playing a disproportionate role.

Conclusions:

• Cognate mRNA/protein sequence complementarity is critically dependent on the properties of the underlying affinity scales.
• The findings support the hypothesis that sequence complementarity relates to mRNA-protein binding.
• Quantitative constraints for physical scales that facilitate complementarity were identified.