Thermodynamics and neutral sets in the RNA sequence-structure map

¹ Theory of Condensed Matter Group, Cavendish Laboratory, University of Cambridge - Cambridge CB3 0HE, UK
² Sainsbury Laboratory, University of Cambridge - Cambridge CB2 1LR, UK
³ Department of Chemical Engineering and Biotechnology, University of Cambridge - Cambridge CB3 0AS, UK
⁴ The Alan Turing Institute, British Library - London NW1 2DB, UK

Received: 2 May 2022
Accepted: 27 June 2022

Abstract

The sequence-structure map of biological macromolecules, also referred to as a genotype-phenotype (GP) map, shapes evolutionary processes by determining how mutations affect molecular structures. RNA secondary structure constitutes a central model in the field, both because of the availability of efficient folding algorithms and the biological importance of RNA structures. Despite the immense knowledge about the characteristics of the RNA GP map, there is not enough understanding of how these characteristics emerge from the underlying energetics of RNA folding. In this paper, we fill this gap with a computational study of the connection between the energy gap between the lowest-energy structures, here referred to as the stability, and the characteristics of the GP map. We focus on neutral sets, i.e., sequences that share a structure, and on connected neutral components within neutral sets. We find first that both mean stability and the stability change through point mutations are linked to the size of neutral sets and neutral components and secondly that the typical stability change through mutations depends on structural characteristics. These results contribute to a deeper understanding of the RNA GP map and are relevant for evolutionary processes since stability may be under selection.