Abstract
It has recently been demonstrated that the nucleobase-density profiles of mRNA coding sequences are related in a complementary manner to the nucleobase-affinity profiles of their cognate protein sequences. Based on this, it has been proposed that cognate mRNA/protein pairs may bind in a co-aligned manner, especially if unstructured. Here, we study the dependence of mRNA/protein sequence complementarity on the properties of the nucleobase/amino-acid affinity scales used. Specifically, we sample the space of randomly generated scales by employing a Monte Carlo strategy with a fitness function that depends directly on the level of complementarity. For model organisms representing all three domains of life, we show that even short searches reproducibly converge upon highly optimized scales, implying that the topology of the underlying fitness landscape is decidedly funnel-like. Furthermore, the optimized scales, generated without any consideration of the physicochemical attributes of nucleobases or amino acids, resemble closely the nucleobase/amino-acid binding affinity scales obtained from experimental structures of RNA-protein complexes. This provides support for the claim that mRNA/protein sequence complementarity may indeed be related to binding between the two. Finally, we characterize suboptimal scales and show that intermediate-to-high complementarity can be reached by substantially diverse scales, but with select amino acids contributing disproportionally. Our results expose the dependence of cognate mRNA/protein sequence complementarity on the properties of the underlying nucleobase/amino-acid affinity scales and provide quantitative constraints that any physical scales need to satisfy for the complementarity to hold.
Highlights
The relationship between mRNAs and the proteins they encode is one of the key defining characteristics of life at the molecular level [1,2,3]
We define the constraints that need to be satisfied by physical scales for the complementarity to hold and show that the previously derived nucleobase/aminoacid affinity scales satisfy these constraints
Our work provides a quantitative foundation for understanding the putative messenger RNA/protein complementarity with implications in different areas of RNA/protein biology including transcription, translation, splicing and viral assembly
Summary
The relationship between mRNAs and the proteins they encode is one of the key defining characteristics of life at the molecular level [1,2,3]. We have studied other affinity scales derived by diverse experimental and theoretical approaches: 1) a chromatographically determined scale of amino-acid affinity for pyrimidine (PYR) mimetics pyridines [7], 2) a computationally derived variant of the same scale [8], 3) absolute binding free energy scales between nucleobases and amino-acid sidechain analogs in different solvents [9], and 4) affinity scales obtained from simulated partitioning experiments using realistic RNA nucleobases [10,11] The consensus of these studies has been that the mRNA regions rich in a particular nucleobase or a type of nucleobases (PUR or PYR) tend to encode the protein regions with a pronounced affinity for precisely those or similar bases. Protein regions with a high affinity for the purine base ADE tend to be encoded by mRNA regions rich in PYR bases [5,6]
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