Equilibrium binding equations for peripheral membrane-binding proteins.

Peripheral Membrane-Binding Proteins underlie and regulate many important physiological functions such as the clearance of apoptotic cells, immune activation, and synaptic pruning. Lipid composition and membrane physical properties allow these proteins to distinguish target from non-target cell membranes. However, a general model describing this sensitivity to membrane composition and properties has yet to be developed. Instead, in the literature, different equations are used on a case-by-case basis to measure binding constants that are highly contextual at best and ambiguous at worst, making it difficult to compare results obtained from different studies. Here, we present a general model underlying the association of this class of proteins with lipid membranes that, when applied to a given system, produces the appropriate equation for the lipid composition dependence with well-defined parameters such as dissociation constants. This model allows us to derive the equations commonly used in the field and establish how their parameters are related. Using examples of phosphatidylserine-binding proteins, we show how this model can potentially reveal multiple binding modes, account for calcium coordination between a given protein and its associated lipids, as well as sensitivity for additional lipid species.