AlphaFold2 and Deep Learning for Elucidating Enzyme Conformational Flexibility and Its Application for Design

[Image: see text] The recent success of AlphaFold2 (AF2) and other deep learning (DL) tools in accurately predicting the folded three-dimensional (3D) structure of proteins and enzymes has revolutionized the structural biology and protein design fields. The 3D structure indeed reveals key information on the arrangement of the catalytic machinery of enzymes and which structural elements gate the active site pocket. However, comprehending enzymatic activity requires a detailed knowledge of the chemical steps involved along the catalytic cycle and the exploration of the multiple thermally accessible conformations that enzymes adopt when in solution. In this Perspective, some of the recent studies showing the potential of AF2 in elucidating the conformational landscape of enzymes are provided. Selected examples of the key developments of AF2-based and DL methods for protein design are discussed, as well as a few enzyme design cases. These studies show the potential of AF2 and DL for allowing the routine computational design of efficient enzymes.