Conformational Entropy as a Potential Liability of Computationally Designed Antibodies.
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Lohr, T., Sormanni, P., & Vendruscolo, M. (2022). Conformational Entropy as a Potential Liability of Computationally Designed Antibodies.. Biomolecules, 12 (5) https://doi.org/10.3390/biom12050718
In silico antibody discovery is emerging as a viable alternative to traditional in vivo and in vitro approaches. Many challenges, however, remain open to enabling the properties of designed antibodies to match those produced by the immune system. A major question concerns the structural features of computer-designed complementarity determining regions (CDRs), including the role of conformational entropy in determining the stability and binding affinity of the designed antibodies. To address this problem, we used enhanced-sampling molecular dynamics simulations to compare the free energy landscapes of single-domain antibodies (sdAbs) designed using structure-based (DesAb-HSA-D3) and sequence-based approaches (DesAbO), with that of a nanobody derived from llama immunization (Nb10). Our results indicate that the CDR3 of DesAbO is more conformationally heterogeneous than those of both DesAb-HSA-D3 and Nb10, and the CDR3 of DesAb-HSA-D3 is slightly more dynamic than that of Nb10, which is the original scaffold used for the design of DesAb-HSA-D3. These differences underline the challenges in the rational design of antibodies by revealing the presence of conformational substates likely to have different binding properties and to generate a high entropic cost upon binding.
antibody design, antibody engineering, protein design, metadynamics, molecular dynamics
External DOI: https://doi.org/10.3390/biom12050718
This record's URL: https://www.repository.cam.ac.uk/handle/1810/337331
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