A Hydrophobic Cluster Modulates Long-Range Allostery in the TRMT2A RNA Recognition Motif

TRMT2A has emerged as a disease-modifying target in polyglutamine (PolyQ) models, yet the conformational preferences and allostery of its RNA recognition motif (RRM) remain poorly resolved. Here, we combine extensive atomistic molecular dynamics with Markov state modeling (MSM), transition path theory, and structure-based pocket analysis to map the conformational landscape of the human TRMT2A RRM. We resolve six metastable states and show that a hydrophobic cluster centered on F92-W134-L133 modulates their interconversion. We further identify residues that contribute to RNA strand recognition and reveal state-specific cryptic pockets consistent with the reported binding sites of TRMT2A RRM small-molecule inhibitors. Together, these results support a hinge-gate model in which a soft, defect-enabled α2 segment and a loop 5 hydrophobic cluster coordinate long-range communication between the ribonucleoprotein (RNP) face and the opposite side, yielding testable mutational predictions and state-specific opportunities for allosteric control of TRMT2A in polyQ disease contexts.