Deciphering the Molecular Basis of Poly(A)-Binding Protein Selectivity for Homopolymeric RNAs.

Protein-RNA interactions are essential for numerous biological processes, including RNA transport, translation, splicing, and gene silencing. Poly(A)-binding proteins (PABPs), a class of RNA-binding proteins, specifically recognize and bind to poly(A) tails, thereby playing a crucial role in mRNA regulation. In this study, we performed molecular dynamics (MD) simulations of PABP complexed with four homopolymeric RNAs, namely, poly(A), poly(G), poly(C), and poly(U), to elucidate the molecular basis underlying PABP's preferential binding toward different RNA analogs. Our simulations of preformed complexes reveal that different RNAs induce distinct conformational responses in PABP, leading to variations in interfacial flexibility and domain coordination. In particular, we demonstrate that complex formation promotes long-range anticorrelated motions among key protein regions, with the most significant effect observed in the poly(A)-bound complex. Importantly, we find poly(G), poly(C), and poly(U) RNAs populate disordered ensembles over the protein surface, forming fuzzy binding interfaces mediated by transient interactions and multiple binding modes, unlike the stable extended binding mode of poly(A) RNA, which is stabilized by favorable base stacking and persistent hydrogen bonding. Such structural and dynamic features are consistent with the enhanced stability of the PABP complex formed with poly(A) RNA, reflecting favorable shape-specific and base-specific interactions. Binding free energy analyses further reveal that the preferential association of PABP with poly(A) involves more favorable hydrophobic contributions and a reduced entropic penalty as compared to association with poly(G), poly(C), and poly(U).