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Cell Syst. 2019 Jan 23;8(1):86-93.e3. doi: 10.1016/j.cels.2018.12.004. Epub 2019 Jan 2.

Epistasis in a Fitness Landscape Defined by Antibody-Antigen Binding Free Energy.

Author information

1
CNRS, Laboratoire de Physique Théorique, UPMC (Sorbonne University), and École Normale Supérieure (PSL), 24 rue Lhomond, Paris 75005, France; Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, 1 Bungtown Rd., Cold Spring Harbor, NY 11724, USA.
2
Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, 1 Bungtown Rd., Cold Spring Harbor, NY 11724, USA.
3
CNRS, Laboratoire de Physique Théorique, UPMC (Sorbonne University), and École Normale Supérieure (PSL), 24 rue Lhomond, Paris 75005, France. Electronic address: awalczak@lpt.ens.fr.
4
CNRS, Laboratoire de Physique Statistique, UPMC (Sorbonne University), Paris-Diderot University, and École Normale Supérieure (PSL), 24, rue Lhomond, Paris 75005, France. Electronic address: tmora@lps.ens.fr.

Abstract

Epistasis is the phenomenon by which the effect of a mutation depends on its genetic background. While it is usually defined in terms of organismal fitness, for single proteins, it must reflect physical interactions among residues. Here, we systematically extract the specific contribution pairwise epistasis makes to the physical affinity of antibody-antigen binding relevant to affinity maturation, a process of accelerated Darwinian evolution. We find that, among competing definitions of affinity, the binding free energy is the most appropriate to describe epistasis. We show that epistasis is pervasive, accounting for 25%-35% of variability, of which a large fraction is beneficial. This work suggests that epistasis both constrains, through negative epistasis, and enlarges, through positive epistasis, the set of possible evolutionary paths that can produce high-affinity sequences during repeated rounds of mutation and selection.

KEYWORDS:

antibody; binding affinity; complementarity-determining regions; epistasis; fitness landscape

PMID:
30611676
DOI:
10.1016/j.cels.2018.12.004

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