The elusive quest for RNA knots

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

It also appears plausible that RNA knots, and other forms of entanglement, are not favored thermodynamically. In fact, independent of kinetic considerations, naturally occurring RNAs appear to be primed for acquiring native structures with rather low geometrical complexity. This observation is prompted by the analysis of secondary-structure predictions of algorithms that are exclusively based on the minimization of the (model) free energy of RNA sequences. These phenomenological approaches clearly do not account for any kinetic effects and yet their returned structures are geometrically much simpler than randomly reshuffled variants of the sequences. For instance, even when using structure prediction algorithms based on planar graph representations one observes that viral RNA sequences have a significantly smaller graph diameter, a proxy for three-dimensional size, than their reshuffled versions. 25, 26 This point is reinforced by the analysis of the minimum energy structures returned by McGenus. 27, 28 Specifically, it is found that the predicted non-planar graphs of the reshuffled variants have a topological complexity, as measured by the graph genus, that is more than an order of magnitude larger than for the wild-type counterparts. 20 Although RNA knots may be elusive today, it is conceivable that they were important in earlier evolutionary stages, even during the origins of life. The RNA world concept posits a period of time when RNA, or something chemically similar, was responsible for all living processes including heredity and metabolism. RNA-RNA interactions have often been proposed to be critical to maintaining the physical integrity of networks of distinct sequences. [29] [30] [31] Typically these interactions have focused solely on secondary structure interactions, but many environments on an early Earth could have experienced rather extreme temperature fluctuations that could disrupt weak basepairing. More severe entanglements such as knotsbut without covalent bondingwould have been a means to preserve spatial sympatry of RNA network individuals in harsh environments. The observation that many catalytic RNA species have structures that are pseudoknotted seems to hint at closer interand intra-molecule associations as one goes back in time.