Harmonic Self-Conditioned Flow Matching for Multi-Ligand Docking and Binding Site Design

A significant amount of protein function requires binding small molecules, including enzymatic catalysis. As such, designing binding pockets for small molecules has several impactful applications ranging from drug synthesis to energy storage. Designing proteins that can bind small molecules has many applications, ranging from drug synthesis to energy storage or gene editing. Indeed, a key part of any protein's function derives from its ability to bind and interact with other molecular species. For example, we may design proteins that act as antidotes that sequester toxins or design enzymes that enable chemical reactions through catalysis, which plays a major role in most biological processes. Specifically, we aim to design protein pockets to bind a certain small molecule (called ligand). We assume that we are given a protein pocket via the 3D backbone atom locations of its residues as well as the 2D chemical graph of the ligand. We do not assume any knowledge of the 3D structure or the binding pose of the ligand. Based on this information, our goal is to predict the amino acid identities for the given backbone locations (see Figure 1). We also consider the more challenging task of designing pockets that simultaneously bind multiple molecules and ions (which we call multi-ligand). Such multi-ligand binding proteins are important, for example, in enzyme design, where the ligands correspond to reactants.