Computational Characterization of Pathogenic LMNA Missense Variants: Structural Instability, Altered Binding, and Conformational Dynamics.

Background: Mutations in the Methods: An integrated multistep in silico framework was employed to investigate the structural and functional consequences of Results: Evo2-based screening of the full LMNA coding sequence identified 50 high-priority loss-of-function variants, of which N456D, N456T, and G465D were retained for structural investigation based on their globular domain localization and multitool pathogenicity predictions. All three variants were consistently predicted to alter physicochemical properties and reduce structural stability relative to wild-type Lamin A. Molecular docking revealed mutation-dependent changes in lonafarnib binding profiles. The known pathogenic control M540T exhibited comparable structural and dynamic behavior, supporting the reliability of the prioritization workflow. Molecular dynamics analyses demonstrated altered RMSD trajectories, increased residue-level flexibility, and modified hydrogen bonding patterns in mutant systems. Free-energy landscape analyses revealed expanded conformational basins, particularly pronounced in the G465D variant, indicating increased structural plasticity. Conclusion: This integrated computational framework provides a systematic strategy for prioritizing pathogenic