Physical epistatic landscape of antibody binding affinity

  title={Physical epistatic landscape of antibody binding affinity},
  author={Rhys M. Adams and Justin B. Kinney and Aleksandra M. Walczak and Thierry Mora},
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… 
An antigenic atlas of HIV-1 escape from broadly neutralizing antibodies
This map maps how all single amino-acid mutations to Env affect neutralization of HIV by nine bnAbs targeting five epitopes and provides a comprehensive dataset for understanding viral immune escape and refining therapies and vaccines.
Inferring the shape of global epistasis
To infer the shape of such global epistasis in three proteins, based on published high-throughput mutagenesis data, a maximum-likelihood inference procedure is developed using a flexible family of monotonic nonlinear functions spanned by an I-spline basis.
Inferring protein stability and function from a high-throughput assay
A statistical method is introduced to infer the underlying biophysics from a high-throughput binding assay by combining information from many mutated variants providing a detailed view of how mutations affect binding and stability across the protein.
Tuning environmental timescales to evolve and maintain generalists
It is found that changing environments on timescales comparable with evolutionary transients in a population enhance the rate of evolving generalists from specialists, without enhancing the reverse process.
Sparse epistatic patterns in the evolution of terpene synthases.
This work has carried out in-depth examination of mutational space around (E)-β-farnesene synthase, an Artemisia annua enzyme which catalyzes production of a linear hydrocarbon chain, and developed biophysical fitness models based on the assumption that highly fit enzymes have evolved to maximize the output of correct products, such as cyclic products or a specific product of interest, while minimizing theoutput of byproducts.
Progress and open problems in evolutionary dynamics.
Key theoretical models of population genetics and evolution are reviewed along with examples of data from lab evolution experiments, longitudinal sampling of viral populations, microbial communities and the studies of immune repertoires.


Measuring the sequence-affinity landscape of antibodies with massively parallel titration curves
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.
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
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
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
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
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
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.