Efficient affinity maturation of antibody variable domains requires co-selection of compensatory mutations to maintain thermodynamic stability.

ABSTRACT: The ability of antibodies to accumulate affinity-enhancing mutations in their complementarity-determining regions (CDRs) without compromising thermodynamic stability is critical to their natural function. However, it is unclear if affinity mutations in the hypervariable CDRs generally impact antibody stability and to what extent additional compensatory mutations are required to maintain stability during affinity maturation. Here we have experimentally and computationally evaluated the functional contributions of mutations acquired by a human variable (V_H) domain that was evolved using strong selections for enhanced stability and affinity for the Alzheimer's Aβ42 peptide. Interestingly, half of the key affinity mutations in the CDRs were destabilizing. Moreover, the destabilizing

SUBMITTER: Julian MC 

PROVIDER: S-EPMC5368667 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature