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

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  • Lukas Bartonek
  • Bojan Zagrovic

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.Author summary: Messenger RNAs and proteins, two essential types of biopolymers, have recently been shown to exhibit closely related, complementary physicochemical properties. Specifically, density profiles of certain groups in messenger RNA sequences directly match the affinity profiles for precisely those groups in protein sequences they encode. Based on this, it has been suggested that these molecules may interact with each other specifically and in a co-aligned fashion, especially when unstructured. Here, we explore different amino-acid scales used in the above analysis to assess which of their properties dictate the observed matching. Specifically, we define the constraints that need to be satisfied by physical scales for the complementarity to hold and show that the previously derived nucleobase/amino-acid affinity scales indeed satisfy these constraints. As a whole, 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.

Suggested Citation

  • Lukas Bartonek & Bojan Zagrovic, 2017. "mRNA/protein sequence complementarity and its determinants: The impact of affinity scales," PLOS Computational Biology, Public Library of Science, vol. 13(7), pages 1-16, July.
  • Handle: RePEc:plo:pcbi00:1005648
    DOI: 10.1371/journal.pcbi.1005648
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    References listed on IDEAS

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    1. Anton A. Polyansky & Mario Hlevnjak & Bojan Zagrovic, 2013. "Analogue encoding of physicochemical properties of proteins in their cognate messenger RNAs," Nature Communications, Nature, vol. 4(1), pages 1-11, December.
    2. Kanani K. M. Lee, 2009. "The enigma of D′′," Nature, Nature, vol. 462(7274), pages 731-732, December.
    3. Benedikt M. Beckmann & Rastislav Horos & Bernd Fischer & Alfredo Castello & Katrin Eichelbaum & Anne-Marie Alleaume & Thomas Schwarzl & Tomaž Curk & Sophia Foehr & Wolfgang Huber & Jeroen Krijgsveld &, 2015. "The RNA-binding proteomes from yeast to man harbour conserved enigmRBPs," Nature Communications, Nature, vol. 6(1), pages 1-9, December.
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