RNA order regulates its interactions with zwitterionic lipid bilayers

RNA-lipid interactions directly influence RNA activity, which plays a crucial role in developing new applications in medicine and biotechnology. However, while specific preferential behaviors between RNA and lipid bilayers have been identified experimentally, their molecular origin remains unexplored. Here we use molecular dynamics simulations to investigate the interaction between RNA and membranes composed of zwitterionic lipids at the atomistic level. Our data reproduce and rationalize previous experimental observations, including that short-chain RNAs rich in guanine have higher affinity for gel-phase membranes compared to RNA sequences rich in other nucleotides and that RNA prefers gel-phase membranes to fluid bilayers. Our simulations reveal that RNA order is a key molecular determinant of RNA-zwitterionic phospholipid interactions. Our data provides a wealth of information at the atomic level that will help accelerating research on RNA-lipid assemblies for task-specific applications such as designing lipid-based nanocarriers for RNA delivery.