The elusive quest for RNA knots

Burton, Aaron S.; Di Stefano, Marco; Lehman, Niles; Orland, Henri; Micheletti, Cristian

In conclusion, the lack of physical knots in presently available RNA structures is particularly intriguing and also unexpected by comparison with other biopolymers, such as proteins and encapsidated viral DNA where knots are known to occur. It is possible that the sequence of naturally-occurring RNAs, some of which need to be efficiently translocated through biological pores, have evolved to harness folding kinetics and thermodynamics so as to minimize the incidence of various forms of selfentanglement, including knots, in their native structures. At the same time, the fact that knotted RNAs with as few as »100 nucleotides have been successfully designed and synthesized, 35 suggests that there is no fundamental reason why relatively short knotted RNAs should not exist in nature, possibly in circularised form where knots could be essential to enhance their mechanical stability. According to this standpoint, the current situation would parallel the historic route taken for proteins, where the occurrence of knots was once deemed implausible, if not impossible, due to the inevitable initial limitations in size and representation bias of the set of available protein structures. To aid the ongoing efforts to detect knotted RNAs we have presented a list of sequences whose predicted native structures are expectedly susceptible to the formation of knots, possibly as isoform competing with other unknotted ones. 40 We hope that the list of selected candidates will serve as a useful starting point toward the systematic search of RNA knots.