Noncovalent Keystone Interactions Controlling Biomembrane Structure

There is a biomedical need to develop molecular recognition systems that selectively target the interfaces of protein and lipid aggregates in biomembranes. This is an extremely challenging problem in supramolecular chemistry because the biological membrane is a complex dynamic assembly of multifarious molecular components with local inhomogeneity. Two simplifying concepts are presented as a framework for basing molecular design strategies. The first generalization is that association of two binding partners in a biomembrane will be dominated by one type of non‐covalent interaction which is referred to as the keystone interaction. Structural mutations in membrane proteins that alter the strength of this keystone interaction will likely have a major effect on biological activity and often will be associated with disease. The second generalization is to view the structure of a cell membrane as three spatial regions, that is, the polar membrane surface, the midpolar interfacial region and the non‐polar membrane interior. Each region has a distinct dielectric, and the dominating keystone interaction between binding partners will be different. At the highly polar membrane surface, the keystone interactions between charged binding partners are ion‐ion and ion–dipole interactions; whereas, ion–dipole and ionic hydrogen bonding are very influential at the mid‐polar interfacial region. In the non‐polar membrane interior, van der Waals forces and neutral hydrogen bonding are the keystone interactions that often drive molecular association. Selected examples of lipid and transmembrane protein association systems are described to illustrate how the association thermodynamics and kinetics are dominated by these keystone noncovalent interactions. How to target biomembranes: It is very challenging to design molecular recognition systems that associate selectively with one structural component of a biomembrane. A simplifying strategy is to focus on the keystone interactions in the three spatial regions of the bilayer (see figure).