Transactive　response　DNA　binding　protein　43　(TDP-43),　an　alternative-splicing　regulator,　can　specifically　bind　long　UG-rich　RNAs,　associated　with　a　range　of　neurodegenerative　diseases.　Upon　binding　RNA,　TDP-43　undergoes　a　large　conformational　change　with　two　RNA　recognition　motifs　(RRMs)　connected　by　a　long　linker　rearranged,　strengthening　the　binding　affinity　of　TDP-43　with　RNA.　We　extend　the　equally　weighted　multiscale　elastic　network　model　(ewmENM),　including　its　Gaussian　network　model　(ewmGNM)　and　Anisotropic　network　model　(ewmANM),　with　the　multiscale　effect　of　interactions　considered,　to　the　characterization　of　the　dynamics　of　binding　interactions　of　TDP-43　and　RNA.　The　results　reveal　upon　RNA　binding　a　loss　of　flexibility　occurs　to　TDP-43＇s　loop3　segments　rich　in　positively　charged　residues　and　C-terminal　of　high　flexibility,　suggesting　their　anchoring　RNA,　induced　fit　and　conformational　adjustment　roles　in　recognizing　RNA.　Additionally,　based　on　movement　coupling　analyses,　it　is　found　that　RNA　binding　strengthens　the　interactions　among　intra-RRM　beta-sheets　and　between　RRMs　partially　through　the　linker＇s　mediating　role,　which　stabilizes　RNA　binding　interface,　facilitating　RNA　binding　efficiency.　In　addition,　utilizing　our　proposed　thermodynamic　cycle　method　combined　with　ewmGNM,　we　identify　the　key　residues　for　RNA　binding　whose　perturbations　induce　a　large　change　in　binding　free　energy.　We　identify　not　only　the　residues　important　for　specific　binding,　but　also　the　ones　critical　for　the　conformational　rearrangement　between　RRMs.　Furthermore,　molecular　dynamics　simulations　are　also　performed　to　validate　and　further　interpret　the　ENM-based　results.　The　study　demonstrates　a　useful　avenue　to　utilize　ewmENM　to　investigate　the　protein-RNA　interaction　dynamics　characteristics.