Development of an integrated structural biology platform specialized for sub-100 kDa protein complexes to support biologics discovery and rational engineering

Abstract

Background: Developing a biologic medicine requires successful decision making at early stages. Knowing structural information for discovery candidates greatly increases the probability of success. Methods: We have evaluated and integrated various structural biology and computation tools and established a cost-effective platform that allows us to obtain fast and accurate structural information for nearly all our biologics projects. Results: We report four case studies selected from 38 projects and share how we integrate cryo-EM structure determination, computational modeling, and molecular dynamics simulation. With proper decision making and strategic planning, the platform allows to obtain results within days to weeks, including sub-100 kDa complexes. Conclusions: Our utilization of this differential approach and multiple software packages allows to manage priorities and resources to achieve goals efficiently. We demonstrate how to overcome particle orientation bias by altering complex composition. In several of our examples, we use glycan density and protein information to facilitate interpretation of low-resolution 3D maps.