Journal
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
Volume 79, Issue 3, Pages 821-829Publisher
WILEY
DOI: 10.1002/prot.22920
Keywords
antibody maturation; somatic mutations; flexibility; molecular dynamics; 48G7; 28B4; AZ28; 4G12; CDR H3
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Funding
- Sandler Program in Basic Sciences
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Prior studies suggest that antibody affinity maturation is achieved, in part, via prearranging the CDRs for binding. The implication is that the entropy cost of binding is reduced and that this rigidification occurs as a consequence of somatic mutations during maturation. However, how these mutations modulate CDR flexibility is unclear. Here, molecular dynamics simulations captured CDR flexibility differences between four mature antibodies (7G12, AZ28, 28B4, and 48G7) and their germline predecessors. Analysis of their trajectories: (1) rationalized how mutations during affinity maturation restrict CDR motility, (2) captured the equilibrium between bound and unbound conformations for the H3 loop of unliganded 7G12, and (3) predicted a set of new mutations that, according to our simulations, should diminish binding by increasing flexibility.
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