Physical epistatic landscape of antibody binding affinity

@article{Adams2017PhysicalEL,
  title={Physical epistatic landscape of antibody binding affinity},
  author={Rhys M. Adams and Justin B. Kinney and Aleksandra M. Walczak and Thierry Mora},
  journal={bioRxiv},
  year={2017}
}
Affinity maturation produces antibodies that bind antigens with high specificity by accumulating mutations in the antibody sequence. Mapping out the antibody-antigen affinity landscape can give us insight into the accessible paths during this rapid evolutionary process. By developing a carefully controlled null model for noninteracting mutations, we characterized epistasis in affinity measurements of a large library of antibody variants obtained by Tite-Seq, a recently introduced Deep… 
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References

SHOWING 1-10 OF 57 REFERENCES
Measuring the sequence-affinity landscape of antibodies with massively parallel titration curves
TLDR
This work describes a new experimental approach, called TiteSeq, that is capable of measuring binding titration curves and corresponding affinities for thousands of variant antibodies in parallel and suggests a role for secondary CDR loops in establishing antibody stability.
Directed evolution of antibody fragments with monovalent femtomolar antigen-binding affinity.
TLDR
Single-chain antibody mutants have been evolved in vitro with antigen-binding equilibrium dissociation constant K(d) = 48 fM and slower dissociation kinetics than those for the streptavidin-biotin complex, demonstrating that the antibody Fv architecture is not intrinsically responsible for an antigen- binding affinity ceiling during in vivo affinity maturation.
Maximum-Entropy Models of Sequenced Immune Repertoires Predict Antigen-Antibody Affinity
TLDR
This work proposes a new statistical approach based on maximum entropy modeling in which a scoring function related to the binding affinity of antibodies against a specific antigen is inferred from a sample of sequences of the immune repertoire of an individual.
A systematic survey of an intragenic epistatic landscape
TLDR
The distribution of intragenic epistatic effects within this region in seven Hsp90 point mutant backgrounds of neutral to slightly deleterious effect is reported and discussed, resulting in an analysis of more than 1000 double-mutants.
Substantial energetic improvement with minimal structural perturbation in a high affinity mutant antibody.
Robustness–epistasis link shapes the fitness landscape of a randomly drifting protein
TLDR
A new model is proposed in which the mutational robustness observed in proteins, and other biological systems, is due primarily to a stability margin, or threshold, that buffers the deleterious physico-chemical effects of mutations on fitness.
The spatial architecture of protein function and adaptation
TLDR
A high-throughput quantitative method is developed for a comprehensive single-mutation study in which every position is substituted individually to every other amino acid and shows that sector positions are functionally sensitive to mutation, whereas non-sector positions are more tolerant to substitution.
Stability-mediated epistasis constrains the evolution of an influenza protein
TLDR
This work created all intermediates along a 39-mutation evolutionary trajectory of influenza nucleoprotein, and introduced each mutation individually into the parent, painting a coherent portrait of epistasis during nucleop protein evolution.
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