Conformational Entropy as a Potential Liability of Computationally Designed Antibodies
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...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-05-01
|
| Series: | Biomolecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2218-273X/12/5/718 |
| _version_ | 1797501214124933120 |
|---|---|
| author | Thomas Löhr Pietro Sormanni Michele Vendruscolo |
| author_facet | Thomas Löhr Pietro Sormanni Michele Vendruscolo |
| author_sort | Thomas Löhr |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T03:15:09Z |
| format | Article |
| id | doaj.art-027aebe76d544a078ba9fd8b48231b47 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T03:15:09Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-027aebe76d544a078ba9fd8b48231b472023-11-23T10:14:33ZengMDPI AGBiomolecules2218-273X2022-05-0112571810.3390/biom12050718Conformational Entropy as a Potential Liability of Computationally Designed AntibodiesThomas Löhr0Pietro Sormanni1Michele Vendruscolo2Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UKDepartment of Chemistry, University of Cambridge, Cambridge CB2 1EW, UKDepartment of Chemistry, University of Cambridge, Cambridge CB2 1EW, UKIn 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.https://www.mdpi.com/2218-273X/12/5/718antibody designantibody engineeringprotein designmetadynamicsmolecular dynamics |
| spellingShingle | Thomas Löhr Pietro Sormanni Michele Vendruscolo Conformational Entropy as a Potential Liability of Computationally Designed Antibodies Biomolecules antibody design antibody engineering protein design metadynamics molecular dynamics |
| title | Conformational Entropy as a Potential Liability of Computationally Designed Antibodies |
| title_full | Conformational Entropy as a Potential Liability of Computationally Designed Antibodies |
| title_fullStr | Conformational Entropy as a Potential Liability of Computationally Designed Antibodies |
| title_full_unstemmed | Conformational Entropy as a Potential Liability of Computationally Designed Antibodies |
| title_short | Conformational Entropy as a Potential Liability of Computationally Designed Antibodies |
| title_sort | conformational entropy as a potential liability of computationally designed antibodies |
| topic | antibody design antibody engineering protein design metadynamics molecular dynamics |
| url | https://www.mdpi.com/2218-273X/12/5/718 |
| work_keys_str_mv | AT thomaslohr conformationalentropyasapotentialliabilityofcomputationallydesignedantibodies AT pietrosormanni conformationalentropyasapotentialliabilityofcomputationallydesignedantibodies AT michelevendruscolo conformationalentropyasapotentialliabilityofcomputationallydesignedantibodies |