Transitions of CDR-L3 Loop Canonical Cluster Conformations on the Micro-to-Millisecond Timescale

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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.

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Fernández-Quintero, M. L., Math, B. A., Loeffler, J. R., & Liedl, K. R. (2019). Transitions of CDR-L3 Loop Canonical Cluster Conformations on the Micro-to-Millisecond Timescale. Frontiers in Immunology, 10. https://doi.org/10.3389/fimmu.2019.02652

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