Premium
Effects of somatic mutations on CDR loop flexibility during affinity maturation
Author(s) -
Wong Sergio E.,
Sellers Ben D.,
Jacobson Matthew P.
Publication year - 2011
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.22920
Subject(s) - affinity maturation , somatic cell , germline , molecular dynamics , mutation , flexibility (engineering) , chemistry , biology , microbiology and biotechnology , biophysics , genetics , antibody , gene , computational chemistry , statistics , mathematics
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. Proteins 2011. © 2010 Wiley‐Liss, Inc.