Length-dependent motions of SARS-CoV-2 frameshifting RNA pseudoknot and alternative conformations suggest avenues for frameshifting suppression

Conserved SARS-CoV-2 RNA regions of critical biological functions define excellent targets for anti-viral therapeutics against Covid-19 variants. One such region is the frameshifting element (FSE), responsible for correct translation of viral polyproteins. Here, we analyze molecular-dynamics motions of three FSE conformations, discovered by graph-theory analysis, and associated mutants designed by graph-based inverse folding: two distinct 3-stem H-type pseudoknots and a 3-way junction. We find that the prevalent H-type pseudoknot in literature adopts ring-like conformations, which in combination with 5′ end threading could promote ribosomal pausing. An inherent shape switch from “L” to linear that may help trigger the frameshifting is suppressed in our designed mutant. The alternative conformation trajectories suggest a stable intermediate structure with mixed stem interactions of all three conformations, pointing to a possible transition pathway during ribosomal translation. These observations provide new insights into anti-viral strategies and frameshifting mechanisms.

A toy-inspired kirigami pattern and its kinematic performance by applying mechanisms and machine theory

Origami that can form various shapes by setting simple creases on the paper and folding along these creases has a lot of applications from the fields of art to engineering. The inverse problem of origami that determines the distribution of creases based on the desired shape is very complicated. In this paper, we use theoretical kinematics to systematically analyse an inverse folding problem of a toy about how to fold a piece of paper into a disc through a smaller hole without breaking it. The results show that some four-crease and six-crease patterns can achieve the expected function, and they can be easily folded with 1 degree of freedom (DOF). It not only opens up a new way to solve the inverse folding problem but also helps students to understand mechanisms and machine theory.

An unexpectedly effective Monte Carlo technique for the RNA inverse folding problem

Solving the RNA inverse folding problem, also known as the RNA design problem, is critical to advance several scientific fields like bioengineering, yet existing approaches have had limited success. The problem has several features that resist traditional computational techniques, such as its exponential complexity and the chaotic behavior of its cost function. Although some state-of-the-art AI approaches have reported promising results, all existing computational methods substantially underperform expert human designers. I combine a different technique, Nested Monte Carlo Search (NMCS), with domain-specific knowledge to create an algorithm that outperforms all prior published methods by wide margins and solves 95 of the 100 puzzles listed in a recently proposed RNA solving difficulty benchmark.

Fatgraph models of RNA structure

In this review paper we discuss fatgraphs as a conceptual framework for RNA structures. We discuss various notions of coarse-grained RNA structures and relate them to fatgraphs.We motivate and discuss the main intuition behind the fatgraph model and showcase its applicability to canonical as well as noncanonical base pairs. Recent discoveries regarding novel recursions of pseudoknotted (pk) configurations as well as their translation into context-free grammars for pk-structures are discussed. This is shown to allow for extending the concept of partition functions of sequences w.r.t. a fixed structure having non-crossing arcs to pk-structures. We discuss minimum free energy folding of pk-structures and combine these above results outlining how to obtain an inverse folding algorithm for PK structures.