Abstract
Sequence and structural diversity of antibodies are concentrated on six hypervariable loops, also known as the complementarity determining regions (CDRs). Five of six antibody CDR loops presumably adopt a so-called canonical structure out of a limited number of conformations. However, here we show for four antibody CDR-L3 loops differing in length and sequence, that each loop undergoes conformational transitions between different canonical structures. By extensive sampling in combination with Markov-state models we reconstruct the kinetics and probabilities of the transitions between canonical structures. Additionally, for these four CDR-L3 loops, we identify all relevant conformations in solution. Thereby we extend the model of static canonical structures to a dynamic conformational ensemble as a new paradigm in the field of antibody structure design.
Highlights
Antibodies have become key players as therapeutic agents and the understanding of the antigen-binding process is crucial [1, 2]
We focused on the Complementary determining region (CDR)-L3 loop, because it reveals a diversity in sequence and structure comparable to the CDR-H3 loop
As a second antibody Antibody variable fragment (Fv) fragment to characterize the CDR-L3 loop ensemble in solution, the antibody binding to lymphocyte function—associated antigen-1 integrin (LFA-1 integrin) was analyzed
Summary
Antibodies have become key players as therapeutic agents and the understanding of the antigen-binding process is crucial [1, 2]. The antibody binding site consists of six hypervariable loops, each three on the variable domains of the heavy (VH) and the light chain (VL) that shape the antigen binding site, the paratope [2,3,4,5]. Five of the six antibody CDR loops can adopt a limited number of main-chain conformations known as canonical structures, except of the CDR-H3 loop [6,7,8]. The CDR-H3 loop, due to its high diversity in length, sequence and structure and its ability to adopt various different conformations during the V(D)J recombination and somatic hypermutation, remains challenging to predict accurately [9,10,11,12,13]. The most prominent CDR-L3 loop length consists of nine residues and can adopt six possible canonical clusters. The genes encoding the two light chains are located on separate
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