Abstract

Phospholipase A2 (PLA2) enzymes play a critical role in cellular signaling and inflammation by hydrolyzing membrane phospholipids, a process fundamentally dependent on their selective interaction with the lipid bilayer. This study addresses the challenge of quantifying this selectivity, particularly in mixed membranes relevant to biological systems. The objective was to estimate the selectivity of PLA2 isoforms for 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-rac-glycerol (POPG) membranes, which mimic zwitterionic and anionic lipid environments, respectively. We employed a computational approach utilizing the novel **Interaction Map** method, which is derived from molecular dynamics simulations. This method allows for the detailed, residue-level mapping of the enzyme's membrane-binding surface and its energetic preference for specific lipid components. The key finding is the quantitative differentiation of PLA2 selectivity, demonstrating how the enzyme's interfacial binding site composition—specifically its distribution of hydrophobic and positively charged residues—dictates its preference for the anionic POPG component over the neutral POPC. This work provides a robust, high-resolution tool for predicting enzyme-membrane interactions, offering significant implications for understanding the regulation of PLA2 activity in cell biology and for the rational design of anti-inflammatory therapeutics targeting these enzymes.