Molecular Dynamics Simulations of RNA-Recognition Motif Complexed with CAC-Containing RNA

Abstract

The RNA-recognition motifs (RRMs) are the most abundant RNA-binding domains in higher vertebrates, which play diverse roles in post-transcriptional gene expression processes. In this work, the free RRM domain and its RNA-binding complex structure are studied by molecular dynamics (MD) simulations. Principal component analysis (PCA) and Molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) methods were used to explore the dynamical and recognition mechanisms of RRM domain and CAC-containing RNA. Through the motion mode comparison between free RRM domain and complex systems, it's found that the RNA-binding interface of free RRM domain is not stable, especially the C-terminal loop. The C-terminal loop in free RRM domain adopts the conformation similar to that in the complex system. The energy decomposition strategy of MM/PBSA was used to analyze the contribution of each residue or nucleotide. In complex system, 20 residues make favorable contributions for RNA binding, which are positioned on the homodimerization interface (such as Arg38, Glu39 and Lys36) or the RNA-binding interface of RRM domain (such as Phe27, Phe65, Lys100, Thr103 and Lys104). These residues are also reported by the previous experiments, which may form hydrogen bonds or intermolecular stacking interactions with RNA. Meanwhile, 11 residues in RRM domain contribute unfavorable energies for RNA binding. These residues are mainly located on the loop structure or the regions far away to the RNA binding interface. In the energy decomposition of RNA, all of 4 nucleotides make favorable energy contributions. The three nucleotides CAC contribute most of the binding energies, so these 3 nucleotides are more stable than U1 in the representative structures. This study provides some new insights into the RNA recognition mechanisms of RRM domain.