Journal
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
Volume 37, Issue 4, Pages 201-215Publisher
SPRINGER
DOI: 10.1007/s10822-023-00501-9
Keywords
Fab stability; Dissociation mechanism; Interface stability; Antibody design; Molecular dynamics
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This study uses molecular dynamics simulations to investigate the melting process and dissociation mechanisms of antigen binding fragments (Fabs). The results provide insights into the structural changes and key interactions that contribute to the stability of Fabs, and have implications for the design of more stable therapeutic antibodies.
Therapeutic antibodies should not only recognize antigens specifically, but also need to be free from developability issues, such as poor stability. 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-H-V-L and in the C(H)1-C-L 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(H)1-C-L interface that contribute to stabilization. The dissociation of the V-H-V-L or C(H)1-C-L 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. Thus, our proposed mechanisms have broad implications in the development and design of new and more stable antigen binding fragments.
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