Molecular dynamics insights into the recognition mechanism of LARP1 for poly(A) RNA

La-related protein 1 (LARP1) is an important RNA-binding protein involved in post-transcriptional regulation, including RNA stability, translation, and degradation. Although structural studies have provided valuable insights into LARP1-RNA recognition, the dynamic mechanism underlying this interaction remains incompletely understood. Here, all-atom molecular dynamics simulations, MM-GB/SA calculations, per-residue energy decomposition, and hydrogen-bond analyses were used to characterize the WT LARP1-RNA complex and eight alanine mutants. Three or four independent 320 ns trajectories were performed for each RNA-bound system. The WT replicates retained highly similar RNA positions and orientations and yielded a mean ΔG_bind of -16.96 ± 1.67 kcal/mol. Comparison with an apo reference trajectory suggested reduced flexibility around the RNA-binding interface. Direct electrostatic and van der Waals interactions favored the binding, whereas polar solvation and conformational entropy opposed binding. Energy decomposition of WT identified Q333, Y336, Y337, D346, F348, F367, H368, and R369 as key contributors, with R369 and Y337 making the strongest favorable contributions. Mutation effects were strongly state dependent. F348A showed a reproducible weakening of binding, whereas Y337A, D346A, and F367A sampled structurally heterogeneous states, including alternative, flipped, or substantially displaced RNA configurations. Overall, the independent simulations demonstrate that mutation of hotspot residues remodels the cooperative LARP1-RNA recognition network and alters the ability of RNA to retain its native pocket-associated orientation.