Reconstruction of Natural RNA Sequences from RNA Shape, Thermodynamic Stability, Mutational Robustness, and Linguistic Complexity by Evolutionary Computation

Abstract

The process of designing novel RNA sequences by inverse RNA folding, available in tools such as RNAinverse and InfoRNA, can be thought of as a reconstruction of RNAs from secondary structure. In this reconstruction problem, no physical measures are considered as additional constraints that are independent of structure, aside of the goal to reach the same secondary structure as the input using energy minimization methods. An extension of the reconstruction problem can be formulated since in many cases of natural RNAs, it is desired to analyze the sequence and structure of RNA molecules using various physical quantifiable measures. In prior works that used secondary structure predictions, it has been shown that natural RNAs differ significantly from random RNAs in some of these measures. Thus, we relax the problem of reconstructing RNAs from secondary structure into reconstructing RNAs from shapes, and in turn incorporate physical quantities as constraints. This allows for the design of novel RNA sequences by inverse folding while considering various physical quantities of interest such as thermodynamic stability, mutational robustness, and linguistic complexity. At the expense of altering the number of nucleotides in stems and loops, for example, physical measures can be taken into account. We use evolutionary computation for the new reconstruction problem and illustrate the procedure on various natural RNAs.

RNAexinv: An extended inverse RNA folding from shape and physical attributes to sequences

“…The comparison depicted in Figure 4 was performed for an miR-146 example test case taken from [15], after it was verified in [9] by taking a collection of miRNAs from the microRNA registry [16] that miRNA precursors are significantly more thermodynamically stable and mutationally robust than random RNAs. Therefore, even though from an initial inspection of the structure drawings in Figure 4 it may appear that the RNAinverse result is in better agreement to the wild-type than the RNAexinv result, it should be noted that the values of the thermodynamic stability and mutational robustness of miR-146 are not taken into account when designing sequences with RNAinverse.…”

“…To incorporate the physical measures listed above as constraints in the inverse RNA folding problem, the problem must first be relaxed from secondary structure to shape, as our previous simulations showed that such constraints can yield no solution [9]. Thus, instead of the RNA secondary structure, we used the simplified coarse-grained representation [13,14] as its shape.…”

“…It should be noted that both RNAinverse [5] and INFO-RNA [7] contain a p-mode option, where the objective function is including the probability that the target structure forms, thus considering thermodynamic stability. Recently, inspired by the physical aspects of RNA secondary structure [8], an extended inverse RNA folding problem was suggested [9], which adds several non-structural constraints to the desired output in conjunction such as thermodynamic stability and mutational robustness. This extension may help incorporate some important properties of natural RNAs to the design problem.…”

“…Unlike the method in [9] that utilizes parallel evolutionary computation and is relatively expensive, the method described here is closer in type to [5-7] and significantly reduces the computation time relative to [9]. It comprises two phases, the first of which is to identify a good initial candidate whose folding closely resembles that of the desired structure.…”

A Complexity-based Method to Compare RNA Secondary Structures and its Application

“…In particular, in many viruses it is RNA that contains genetic information of virus such as HIV and therefore regulates the functions of such virus. RNA has recently become the center of much attention because of its catalytic properties, leading to an increased interest in obtaining structural information (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Although more and more RNA secondary structures have been accumulated, we know little about their functions.…”