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Thus, the mechanistic understanding and characterization of stability are critical determinants for rational antibody design. In this study, we use molecular dynamics simulations to investigate the melting process of 16 antigen binding fragments (Fabs). We describe the Fab dissociation mechanisms, showing a separation in the V<jats:sub>H<\/jats:sub>\u2013V<jats:sub>L<\/jats:sub> and in the C<jats:sub>H<\/jats:sub>1\u2013C<jats:sub>L<\/jats:sub> domains. We found that the depths of the minima in the free energy curve, corresponding to the bound states, correlate with the experimentally determined melting temperatures. Additionally, we provide a detailed structural description of the dissociation mechanism and identify key interactions in the CDR loops and in the C<jats:sub>H<\/jats:sub>1\u2013C<jats:sub>L<\/jats:sub> interface that contribute to stabilization. The dissociation of the V<jats:sub>H<\/jats:sub>\u2013V<jats:sub>L<\/jats:sub> or C<jats:sub>H<\/jats:sub>1\u2013C<jats:sub>L<\/jats:sub> domains can be represented by conformational changes in the bend angles between the domains. Our findings elucidate the melting process of antigen binding fragments and highlight critical residues in both the variable and constant domains, which are also strongly germline dependent. 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