Rna: Computational Methods for Structure, Kinetics, and Rational Design: Volume Two

Volumes 1 and 2 of "RNA: Computational methods for structure, kinetics, and rational design" together constitute a comprehensive presentation of RNA secondary structures. Volume 1 concerns thermodynamics, energy parameters, methods to count structures, base pairs, loops, leading to many algorithms concerning RNA structure.Volume 2 covers secondary structure folding kinetics, starting with an inquiry into whether the ensemble of RNA structures is small-world or scale-free, then proceeding to the identification of local energy minima that create a basin of attraction, leading to a coarse-grained kinetics model. A novelty is the presentation of Markov state models (MSM) and Transition Path Theory (TPT), developed originally to create coarse-grained kinetics models for (especially) proteins from many independent molecular dynamics trajectories. The book describes Markov state models created from secondary structure folding trajectories generated by the kinetic Monte Carlo (Gillespie) algorithm. As this is the first such application in the literature, our Python code will be made available at the book's website, with the intent that other research teams might use the code to extend this approach. Current RNA research concerns the rational design of functional RNA molecules, which depends on inverse folding algorithms that generate many sequences that (approximately) fold into a given target structure. For that reason, the book provides an overview and comparison of various inverse folding algorithms, which often depend on some form of combinatorial optimization. The question of whether inverse folding is computationally hard (NP-complete) is addressed, and another chapter focuses on various types of designed RNA: ribozymes, RNA thermometers, bistable switches, toehold switches, mRNA vaccines, paper-based COVID-19 tests, etc. The final chapter is a math appendix for the linear algebra and Markov chain results that are essential to folding kinetics, especially in the case of Markov state models. In summary, volume 2 presents the necessary concepts from mathematics and algorithm theory for the next generation of research teams to extend the computational work on RNA, especially for the rational design of functional molecules - a topic that not so long ago seemed more like science fiction. Exercises at the end of each chapter often introduce new material or related concepts, and solutions are available at the book's website.The book includes the first description in the literature (our code dates from Feb, Mar 2021) of the construction of Markov state models (MSM) and transition path theory (TPT) for secondary structure folding trajectories generated by the kinetic Monte Carlo algorithm. Other features include network properties (small-world, scale-free) of the ensemble of secondary structures, a succinct overview and comparison of inverse folding methods, discussion of whether inverse folding is NP-complete, design of ribozymes, thermoswitches, toehold switches, thermodynamically stable mRNA vaccines.