The　YTH　domain　of　YTHDF3　belongs　to　a　class　of　protein　＂readers＂　recognizing　the　N6-methyladenosine　(m(6)A)　modification　in　mRNA.　Although　static　crystal　structure　reveals　m(6)A　recognition　by　a　conserved　aromatic　cage,　the　dynamic　process　in　recognition　and　importance　of　aromatic　cage　residues　are　not　completely　clear.　Here,　molecular　dynamics　(MD)　simulations　are　performed　to　explore　the　issues　and　negative　selectivity　of　YTHDF3　toward　unmethylated　substrate.　Our　results　reveal　that　there　exist　conformation　selectivity　and　induced-fit　in　YTHDF3　binding　with　m(6)A-modified　RNA,　where　recognition　loop　and　loop6　play　important　roles　in　the　specific　recognition.　m(6)A　modification　enhances　the　stability　of　YTHDF3　in　complex　with　RNA.　The　methyl　group　of　m(6)A,　like　a　warhead,　enters　into　the　aromatic　cage　of　YTHDF3,　where　Trp492　anchors　the　methyl　group　and　constraints　m(6)A,　making　m(6)A　further　stabilized　by　pi-pi　stacking　interactions　from　Trp438　and　Trp497.　In　addition,　the　methylation　enhances　the　hydrophobicity　of　adenosine,　facilitating　water　molecules　excluded　out　of　the　aromatic　cage,　which　is　another　reason　for　the　specific　recognition　and　stronger　intermolecular　interaction.　Finally,　the　comparative　analyses　of　hydrogen　bonds　and　binding　free　energy　between　the　methylated　and　unmethylated　complexes　reveal　the　physical　basis　for　the　preferred　recognition　of　m(6)A-modified　RNA　by　YTHDF3.　This　study　sheds　light　on　the　mechanism　by　which　YTHDF3　specifically　recognizes　m(6)A-modified　RNA　and　can　provide　important　information　for　structure-based　drug　design.