Developments in both science and technology have elevated RNA from being considered a mere “messenger” between DNA and proteins, to both the perhaps most important key that there is to understanding cellular function, and the basis of revolutionary technologies ranging from CRISPR to mRNA vaccines. In biology the relatisation that the 98% of genome doesn’t encode for “junk RNA”, rather long non-coding RNA (lncRNA) is emerging as a key component of intracellular membraneless organelles in the cell. The dynamic interactions between lncRNA and various intrinsically disordered proteins (IDP – effectively very long unfolded peptide chains) leads to the formation of condensates that are often referred to as liquid-liquid phase separated (LLPS) droplets. Biologists have started to map out the interactions between RNA and IDP’s but are quickly realising that this challenge requires a physical/supramolecular chemistry approach and a deeper understanding of these systems may not be attainable through conventional structural biology methods.
We will report here on our endeavours to advancing the understanding of how RNA and peptides interact at the (supra)molecular level. This includes probing potential sequence-selectivity and the role of various supramolecular interactions ranging from hydrophobic interactions, hydrogen bonding, electrostatic to aromatic interactions. To date we have done this through studying condensates formed between short peptide such as triglycine-X-triglycines and pentanucleotide RNA oligo’s (e.g., AAXAA), how a tryptophan-zipper peptide mimic of RNA-binding proteins bind to short RNA’s and the dynamic nature of peptide-yeast RNA interactions. These initial studies are already providing valuable new insight into the factors that control RNA-peptide interactions which in the future could underpin the development of therapeutics that would modulate these interactions.