Jul 26 2022 Theoretical studies on RNA recognition by Musashi 1 RNA-binding protein

In this contribution we study the association complexes of the RNA-binding protein Musashi 1 (MSI1) with different RNA motifs, using molecular dynamics simulations

The RNA-binding protein Musashi1 (MSI1) is involved in the maintenance and self-renewal of neuronal progenitor and stem cells. Alongside its endogenous role, it has been shown to enhance the replication of Zika virus (ZIKV), suggesting a crucial role of MSI1:RNA complexes in ZIKV-induced neurotropism.

This paper uses computational modeling to study association complexes of the RNA-binding protein Musashi 1 (MSI1) with different target RNAs. MSI1 has two RNA-binding domains that exhibit different affinities to bind single-stranded #RNA molecules. Here, we investigate MSI1:RNA complexes using different RNA pentamer motifs, employing molecular dynamics simulations with binding free energy calculations. Understanding these RNA-protein complexes is important to explain MSI1-mediated congenital neuropathology, such as microcephaly.

Joint work with Thanyada Rungrotmongkol and Nitchakan Darai (Chulalongkorn University), as well as Peter Wolschann (Universität Wien)

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Abstract

The Musashi (MSI) family of RNA-binding proteins, comprising the two homologs Musashi-1 (MSI1) and Musashi-2 (MSI2), typically regulates translation and is involved in cell proliferation and tumorigenesis. MSI proteins contain two ribonucleoprotein-like RNA-binding domains, RBD1 and RBD2, that bind single-stranded RNA motifs with a central UAG trinucleotide with high affinity and specificity. The finding that MSI also promotes the replication of Zika virus, a neurotropic Flavivirus, has triggered further investigations of the biochemical principles behind MSI–RNA interactions. However, a detailed molecular understanding of the specificity of MSI RBD1/2 interaction with RNA is still missing. Here, we performed computational studies of MSI1–RNA association complexes, investigating different RNA pentamer motifs using molecular dynamics simulations with binding free energy calculations based on the solvated interaction energy method. Simulations with Alphafold2 suggest that predicted MSI protein structures are highly similar to experimentally determined structures. The binding free energies show that two out of four RNA pentamers exhibit a considerably higher binding affinity to MSI1 RBD1 and RBD2, respectively. The obtained structural information on MSI1 RBD1 and RBD2 will be useful for a detailed functional and mechanistic understanding of this type of RNA–protein interactions.

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Theoretical studies on RNA recognition by Musashi 1 RNA–binding protein
Nitchakan Darai, Panupong Mahalapbutr, Peter Wolschann, Vannajan Sanghiran Lee, Michael T. Wolﬁnger, Thanyada Rungrotmongkol
Sci. Rep. 12:12137 (2022) | doi:10.1038/s41598-022-16252-w | PDF

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