Proteins are polymers built from the small, monomeric units of amino acids. These large biomolecules are the fundamental building blocks of all living organisms. They perform a wide range of functions in organisms such as DNA replication, providing cellular structures, catalyzing biochemical reactions, assisting in cell signaling, and immune responses. In the last several decades, there has been a steady improvement in our ability to computationally predict and design their structures. In the last year, the success of Alpha-Fold 2 demonstrated that the rules of protein structures are now sufficiently well understood that they can be predicted with an accuracy matching experimental methods. Now, the focus of computational protein design and engineering is shifting to better model protein interactions and binding. The archetype of binding proteins are antibodies (Abs), also known as immunoglobulins (Igs). These immune system proteins are responsible for protecting the body against infectious, disease causing organisms. They are also widely used as therapeutics, with an annual global market well in excess of $100 billion. Even though Igs are critical for treating diseases, the conventional approach of designing them in the laboratory can be expensive, time consuming, and remains a matter of luck. An alternative to this experimental approach is to use computational methods to design antibodies and other proteins with similar binding mechanisms (e.g. nanobodies, 10th Type III Fibronectin (10Fn3) domains, etc.). The Pantazes research group developed an Algorithm for Ultra-rapid Binding Interaction Engineering (AUBIE) for the fast, de novo design of therapeutic binding proteins. The key focus of the algorithm is on the optimal placement of hotspot binding interactions, enabling the design of high-affinity protein binders. This presentation will describe the algorithm’s database generation and design protocols, as well as discuss the features of designed proteins against a series of peptide and protein antigens, including the receptor binding domain of SARS-CoV-2. The presentation will finish with a vision for how these approaches form the basis for the rapid, rational design of functional proteins.

AUBIE: Overview of an algorithm for the rapid de novo design of binding proteins

ACS Fall 2021

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