AI Protein Design of N-Acetylgalactosamine Deacetylase for Universal Blood Type Conversion

Abstract

Type O blood is the universal donor type, which is crucial in healthcare because it is compatible with any patient.  However, this supply is ever decreasing as blood shortages consume our country. If pre-existing supplies of Type A, B, or AB blood can be converted to Type O, the impact of blood shortages could be significantly reduced, and thousands of lives can be saved. With efforts first initiated almost 50 years ago, an effective enzyme system for the conversion was found in 2019. While currently insufficient to be used in healthcare, the creation of AI programs in just the past few years have revolutionized protein design, allowing for the revitalization of universal blood type conversion. Through LigandMPNN, the first enzyme in the system, N-Acetylgalactosamine Deacetylase, was redesigned to improve binding to the sugars on red blood cells, increasing their removal. With AlphaFold 3’s capability to model proteins with sugars, a competitive binding assay between the mutated protein, the native one, and the blood sugar was performed to filter down the candidates and select the strongest sequence. Such proteins have the potential to make universal blood type conversion a reality.