Hi Matthew Halma

The simplest structures that antibodies can be formed against: Antibodies primarily recognize and bind to epitopes on antigens. An epitope can be as small as a few amino acids in a protein or a small arrangement of sugars in a polysaccharide. Small molecules can also induce an immune response, but they are typically haptens that need to be conjugated to larger carrier proteins to induce antibody production. It's challenging to define the absolute "simplest" structure because the specificity of an antibody doesn't solely depend on the complexity of the antigen, but also on the context in which it's presented and how the immune system processes it. Theoretically imposed lower bound on the informational complexity of an antigen: The specificity and affinity of an antibody towards an antigen depend on the structural fit between the antigen (or epitope) and the antibody's antigen-binding site. Therefore, while there's no strict lower limit on the complexity of an antigen, there's a practical lower limit due to the need for a certain level of structural specificity to ensure the antibody selectively binds the intended antigen and not other similar structures. It's also worth noting that antibodies are typically generated against macromolecules (proteins, polysaccharides, nucleic acids) and not against small molecules or ions. Antibodies against small molecules (like haptens) are usually generated when these molecules are conjugated to a larger carrier protein.

There are two aspects to the response to this question:

1 - requirements for immunogenicity, necessary to get a good immune response in the context of a natural immune system

2 - requirements for the specific molecular interactions between antigen and antibody to achieve sufficiently high affinity and specificity

1 - requirements for immunogenicity

Normally, to get a good immune response, your antigen needs to comprise both B-cell epitopes and T-cell epitopes. The antibodies produced by the B-cell, through differential splicing, also contribute the recognition unit of the B-cell receptor, needed for B-cell activation. B-cell receptor mediated uptake of the antigen. A protein antigen will be proteolytically processed and its peptides displayed by MHC to TH2 T-helper cells. Stimulatory signals from the T-helper cells will trigger somatic hypermutation (affinity maturation), antibody class switch, B-cell proliferation and differentiation into antibody-producing plasma cells and long-lived memory B-cells. Highly polyvalent antigens and antigens that act as B-cell mitogens via Toll-like receptors can activate B-cells in a T-cell independent manner.

By covalently coupling non-proteinacious antigens (Haptens) to a carrier proteins, an immunogenicity is created that combines a polyvalent display of the Hapten with the T-cell epitopes of the carrier protein, allowing these conjugates to induce a robust immune response.

2 - requirements for high affinity and specificity

The interaction energy between antigen and antibody and thereby the binding affinity is limited by the contact surface. Small Haptens are rarely bound with high affinity, and high affinity interactions between antibodies and Haptens are characterized by a binding mode in which the Hapten is deeply buried in the VL/VH interface, thereby maximising the contact surface. While hydrophobic interactions, aka the reduction of solvent exposed hydrophobic surface area, provide the driving force for the binding interaction, they are fairly unspecific. For good specificity, hydrogen bonding and charge interactions are needed.