Functional antibody characterization via direct structural analysis and information-driven protein-protein docking.

Detailed description of the mechanism of action of the therapeutic antibodies is essential for the functional characterization and future optimization of potential clinical agents. We recently developed KD035, a fully human antibody targeting vascular endothelial growth factor receptor 2 (VEGFR2). KD035 blocked VEGF-A, and VEGF-C-mediated VEGFR2 activation, as demonstrated by the in vitro binding and competition assays and functional cellular assays. Here, we report a computational model of the complex between the variable fragment of KD035 (KD035(Fv)) and the domains 2 and 3 of the extracellular portion of VEGFR2 (VEGFR2(D2-3)). Our modeling was guided by a priori experimental information including the X-ray structures of KD035 and related antibodies, binding assays, target domain mapping and comparison of KD035 affinity for VEGFR2 from different species. The accuracy of the model was assessed by molecular dynamics simulations, and subsequently validated by mutagenesis and binding analysis. Importantly, the steps followed during the generation of this model can set a precedent for future in silico efforts aimed at the accurate description of the antibody-antigen and more broadly protein-protein complexes.

Peptide Toxins as Biothreats and the Potential for AI Systems to Enhance Biosecurity.

Biological weapons have been used for thousands of years, but recent advances in synthesis technologies have made peptide and protein toxin production more accessible and pose a threat to biosecurity worldwide. Natural toxins such as conotoxins, certain hemolytic compounds, and enterotoxins are peptide agents that can be synthesized in an environment with weak biosecurity measures and rudimentarily weaponized for limited use against smaller targets for lethal or nonlethal effects. Technological advances are changing the threat landscape around biological weapons and potentially facilitating a shift from state sponsored to more micro-level threats stemming from terror cells, insider threats, and lone wolf attacks. Here, we present the reader with an overview of the threat of peptide and protein toxins, provide examples of potent peptide toxins, and introduce capabilities of a proposed biosecurity program utilizing artificial intelligence that unifies commercial nucleotide and peptide synthesis vendors.