COARSE-GRAINED PARAMETERIZATION OF HYDROPEROXIDIZED POPC FOR THE SIRAH FORCE FIELD

Lipid peroxidation modifies the biophysical properties of biological membranes and modulates the activity of embedded G protein-coupled receptors (GPCRs), yet its impact on peptide-receptor complexes remains computationally unexplored, since the governing phenomena occur on time scales inaccessible to atomistic simulations and coarse-grained (CG) force fields with explicit solvent are scarce for parameters for oxidized lipids. This work describes the parameterization of POPC bearing a hydroperoxyl group at carbon 10 of the oleoyl chain (POOH) for the SIRAH force field. The CG lipid, named CXO, was mapped from the corresponding atomistic structure, requiring two new bead types (E3 and W0) and dedicated beads for the peroxide group; equilibrium angles and force constants of the BGL–BE2–BC21 and BC21–BC22–BC23 angles were refined against an atomistic reference. Oxidized bilayers were simulated for 1 μs (Amber24, SIRAH v2.3, 310 K, 0.15 M NaCl, WT4 water) and compared with 50 ns all-atom trajectories through density profiles, area per lipid, thickness and lipid conformation. CXO reproduced the migration of the peroxyl group towards the lipid–water interface and the chair-like conformation of the oxidized chain, although this state was transient and less prevalent than in atomistic models. Area per lipid was smaller and thickness slightly larger than atomistic values, since extended conformations resembling native POPC predominated, indicating partial reproduction of the oxidized state. CXO provides the first CG description of hydroperoxidized lipids in SIRAH.

This work was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001, by the Rio de Janeiro Research Foundation (FAPERJ), grant E-26/201.155/2021(260675), and by the Brazilian National Council for Scientific and Technological Development (CNPq), grant 305524/2022-4. This work also used computational resources provided by the RPT04A Bioinformatics Core Facility at Fiocruz, Rio.