Biomolecular recognition of the glycan neoantigen CA19-9 by distinct antibodies

ABSTRACTGlycans decorate cell surface, secreted glycoproteins and glycolipids. Altered glycans are often found in cancers. Despite their high diagnostic and therapeutic potentials, glycans are polar and flexible molecules that are quite challenging for the development and design of high-affinity binding antibodies. To understand the mechanisms by which glycan neoantigens are specifically recognized by antibodies, we analyze the biomolecular recognition of a single tumor-associated carbohydrate antigen CA19-9 by two distinct antibodies using X-ray crystallography. Despite the plasticity of glycans and the very different antigen-binding surfaces presented by the antibodies, both structures reveal an essentially identical extended CA19-9 conformer, suggesting that this conformer’s stability selects the antibodies. Starting from the bound structure of one of the antibodies, we use the AbLIFT computational method to design a variant with seven core mutations that exhibited tenfold improved affinity for CA19-9. The results reveal strategies used by antibodies to specifically recognize glycan antigens and show how automated antibody-optimization methods may be used to enhance the clinical potential of existing antibodies.

Integrated protocol to study hydrogen abstraction reactions by atomic hydrogen in flexible molecules: Application to the butanol isomers

This work presents a protocol designed to study hydrogen abstraction reactions by atomic hydrogen in molecules with multiple conformations. The protocol starts with the search and location of the conformers...

AutoGraph: Autonomous Graph Based Clustering of Small-Molecule Conformations

<div> <div> <div> <p>While accurately modeling the conformational ensemble is required for predicting properties of flexible molecules, the optimal method of obtaining the conformational ensemble seems as varied as their applications. Ensemble structures have been modeled by generation, refinement, and clustering of conformations with a sufficient number of samples. We present a conformational clustering algorithm intended to automate the conformational clustering step through the Louvain algorithm, which requires minimal hyperparameters and importantly no predefined number of clusters or threshold values. The conformational graphs produced by this method for O-succinyl-L-homoserine, oxidized nicotinamide adenine dinucleotide, and 200 representative metabolites each preserved the geometric/energetic correlation expected for points on the potential energy surface. Clustering based on these graphs provide partitions informed by the potential energy surface. Automating conformational clustering in a workflow with AutoGraph may mitigate human biases introduced by guess-and-check over hyperparameter selection while allowing flexibility to the result by not imposing predefined criteria other than optimizing the model’s loss function. Associated codes are available at https://github.com/TanemuraKiyoto/AutoGraph . </p> </div> </div> </div>

AutoGraph: Autonomous Graph Based Clustering of Small-Molecule Conformations

<div> <div> <div> <p>While accurately modeling the conformational ensemble is required for predicting properties of flexible molecules, the optimal method of obtaining the conformational ensemble seems as varied as their applications. Ensemble structures have been modeled by generation, refinement, and clustering of conformations with a sufficient number of samples. We present a conformational clustering algorithm intended to automate the conformational clustering step through the Louvain algorithm, which requires minimal hyperparameters and importantly no predefined number of clusters or threshold values. The conformational graphs produced by this method for O-succinyl-L-homoserine, oxidized nicotinamide adenine dinucleotide, and 200 representative metabolites each preserved the geometric/energetic correlation expected for points on the potential energy surface. Clustering based on these graphs provide partitions informed by the potential energy surface. Automating conformational clustering in a workflow with AutoGraph may mitigate human biases introduced by guess-and-check over hyperparameter selection while allowing flexibility to the result by not imposing predefined criteria other than optimizing the model’s loss function. Associated codes are available at https://github.com/TanemuraKiyoto/AutoGraph . </p> </div> </div> </div>