Allosteric mechanism for SL RNA recognition by polypyrimidine tract binding protein RRM1: An atomistic MD simulation and network-based study.

Polypyrimidine tract-binding protein (PTB), an RNA-binding protein, is involved in the regulation of diverse processes in mRNA metabolism. However, the allosteric modulation of its binding with RNA remains unclear. We explore the dynamic characteristics of PTB RNA recognition motif 1 (RRM1) in its RNA-free and wild-type/mutant RNA-bound states to understand the issues using molecular dynamics (MD) simulation, perturbation response scanning (PRS) and protein structure network (PSN) models. It is found that RNA binding strengthens RRM1 stability, while L151G mutation in α3 helix far away from the interface makes the complex unstable. The latter is caused by long-distance dynamic couplings, which makes intermolecular electrostatic and entropy energies unfavorable. The weakened couplings between interface β sheets and C-terminal parts upon mutation reveal RNA recognition is co-regulated by these regions. Interestingly, PRS analysis reveals the allostery caused by the perturbation on α3 helix has already been pre-encoded in the equilibrium dynamics of the protein structure. PSN analysis shows the details of the allosteric signal transmission, revealing the necessity of strong couplings between α3 helix and interface for maintaining the high binding affinity. This study sheds light on the mechanisms of PTB allostery and RNA recognition and can provide important information for drug design.