The Boltzmann distributions of molecular structures predict likely changes through random mutations

• Published in: Biophysical journal Vol. 122; no. 22; pp. 4467 - 4475
• Main Authors: Martin, Nora S, Ahnert, Sebastian E
• Format: Journal Article
• Language: English
• Published: United States The Biophysical Society 21-11-2023
• Subjects: Evolution, Molecular; Models, Genetic; Molecular Structure; Mutation; Nucleic Acid Conformation; RNA - chemistry
• ISSN: 0006-3495; 1542-0086; 1542-0086
• DOI: 10.1016/j.bpj.2023.10.024

New folded molecular structures can only evolve after arising through mutations. This aspect is modeled using genotype-phenotype maps, which connect sequence changes through mutations to changes in molecular structures. Previous work has shown that the likelihood of appearing through mutations can differ by orders of magnitude from structure to structure and that this can affect the outcomes of evolutionary processes. Thus, we focus on the phenotypic mutation probabilities φ
, i.e., the likelihood that a random mutation changes structure p into structure q. For both RNA secondary structures and the HP protein model, we show that a simple biophysical principle can explain and predict how this likelihood depends on the new structure q: φ
is high if sequences that fold into p as the minimum-free-energy structure are likely to have q as an alternative structure with high Boltzmann frequency. This generalizes the existing concept of plastogenetic congruence from individual sequences to the entire neutral spaces of structures. Our result helps us understand why some structural changes are more likely than others, may be useful for estimating these likelihoods via sampling and makes a connection to alternative structures with high Boltzmann frequency, which could be relevant in evolutionary processes.