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dc.contributor.authorLöhr, Thomas
dc.contributor.authorSormanni, Pietro
dc.contributor.authorVendruscolo, Michele
dc.date.accessioned2022-06-29T19:47:36Z
dc.date.available2022-06-29T19:47:36Z
dc.date.issued2022-05-18
dc.identifier.issn2218-273X
dc.identifier.other35625644
dc.identifier.otherPMC9138470
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/338544
dc.description.abstractIn 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.
dc.languageeng
dc.publisherMDPI AG
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceessn: 2218-273X
dc.sourcenlmid: 101596414
dc.subjectAntibody engineering
dc.subjectMolecular dynamics
dc.subjectProtein design
dc.subjectMetadynamics
dc.subjectAntibody Design
dc.subjectComplementarity Determining Regions
dc.subjectAntibodies
dc.subjectMolecular Conformation
dc.subjectEntropy
dc.subjectSingle-Domain Antibodies
dc.titleConformational Entropy as a Potential Liability of Computationally Designed Antibodies.
dc.typeArticle
dc.date.updated2022-06-29T19:47:36Z
prism.issueIdentifier5
prism.publicationNameBiomolecules
prism.volume12
dc.identifier.doi10.17863/CAM.85957
dcterms.dateAccepted2022-05-08
rioxxterms.versionofrecord10.3390/biom12050718
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidLöhr, Thomas [0000-0003-2969-810X]
dc.contributor.orcidSormanni, Pietro [0000-0002-6228-2221]
dc.contributor.orcidVendruscolo, Michele [0000-0002-3616-1610]
dc.identifier.eissn2218-273X
cam.issuedOnline2022-05-18


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International