The computational study of Orb2 isoforms and the mRNA interactions and their role in long-term memory

Long-term memory (LTM) is crucial for storing information over extended periods, and its impairment significantly impacts degenerative diseases like Alzheimer's and Parkinson's. The activation of local protein synthesis in neurites in response to stimulation is essential for LTM formation. Proteins from the CPEB family, such as the Drosophila protein Orb2, are vital in this process. Research has shown that mutations affecting Orb2 can impair LTM. The 3'UTR of Tequila mRNA, is a significant mRNA target of Orb2 and plays an essential role in LTM. Orb2 exists in two isoforms, Orb2A and Orb2B, both containing an N-terminal prion-like domain, but differing in length and biophysical properties. Despite lower neuronal levels, Orb2A forms amyloids more efficiently than Orb2B in vitro and in vivo. Additionally, a mutation (M2) in the Orb2 binding site of the Tequila mRNA 3'UTR significantly reduces its recruitment, highlighting the importance of precise molecular interactions. However, the molecular mechanisms underlying their interactions with the Tequila mRNA 3'UTR, as well as the structural dynamics of these isoforms, remain poorly understood. Therefore, molecular dynamics simulations can offer atomlevel insights into their stability and potential roles in LTM․