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Colorful yet tractable: docking, design and equilibrium statistics of protein-binding ssRNAs

Abstract

We revisit the fragment-based docking and design of single-stranded RNA aptamers (ssR-NAs), consisting of k nucleotides, onto a rigid protein. Individual fragments, representing nucleotides, are docked onto the protein surface using a force field, and some among the resulting n poses are pieced together to form a conformation compatible with the input ssRNA sequence. Relaxing the sequence compatibility constraint, a similar methodology can be used to design ssRNAs that preferentially bind a protein of interest, possibly targeting a pocket. However, a brute-force enumeration of clash-free conformations quickly becomes prohibitive due to their superexponential combinatorial explosion (Θ(n k) conformations), hindering the potential of fragment-based methods. We leverage the elegant color-coding technique, introduced by Alon, Yuster and Zwick to solve the associated problems exactly in time and space linear on n the number of poses, and in time only exponential on k the number of nucleotides. The dynamic programming algorithm at the core of our method is surprisingly simple, and can be extended to produce suboptimal candidates, or to perform stochastic sampling of candidates within a Boltzmann distribution. This sampling procedure can be adapted into a statistically-consistent estimator for virtually any feature of interest. The versatility and practicality of the color coding framework, demonstrated by a successful reanalysis and redesign of documented ssRNA/protein complexes, could be key to the development of future hybrid discrete/continuous methods in structural bioinformatics.
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Dates and versions

hal-03816423 , version 1 (16-10-2022)

Identifiers

  • HAL Id : hal-03816423 , version 1

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Taher Yacoub, Yann Ponty, Fabrice Leclerc, Roy González-Alemán. Colorful yet tractable: docking, design and equilibrium statistics of protein-binding ssRNAs. 2022. ⟨hal-03816423⟩
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