biostudies-literatureUnknownBanerjee PNIAID NIH HHSNIH HHSThe HIV-1 restriction factor, hSERINC3, functions as a lipid scramblase, translocating lipids across the bilayer in reconstituted proteoliposomes and the viral envelope. Phosphatidylserine(PS) scrambling and exposure at the outer leaflet are recognized to play important roles in several biological processes. To understand the mechanistic basis for hSERINC3-mediated PS lipid scrambling at atomistic resolution, we implemented the transition-tempered metadynamics (TTMetaD) enhanced sampling method. Our simulations sampled close-to-open hSERINC3 conformational transition during PS scrambling and demonstrated that while other non-ATP-dependent lipid transporters with similar architecture transport lipid following a "trap-and-flip" mechanism, hSERINC3 adopts a "credit card" mechanism of lipid scbioRxiv : the preprint server for biology2025.11.13.688349https://www.ebi.ac.uk/biostudies/studies/S-EPMC12642633biostudies-literatureMechanism of Phosphatidylserine Lipid Scrambling by Human SERINC3, an HIV-1 Restriction Factor.PMC12642633S10 OD028655U54 AI170855Yeager MVoth GABanerjee PfalseMechanism of Phosphatidylserine Lipid Scrambling by Human SERINC3, an HIV-1 Restriction Factor.The HIV-1 restriction factor, hSERINC3, functions as a lipid scramblase, translocating lipids across the bilayer in reconstituted proteoliposomes and the viral envelope. Phosphatidylserine(PS) scrambling and exposure at the outer leaflet are recognized to play important roles in several biological processes. To understand the mechanistic basis for hSERINC3-mediated PS lipid scrambling at atomistic resolution, we implemented the transition-tempered metadynamics (TTMetaD) enhanced sampling method. Our simulations sampled close-to-open hSERINC3 conformational transition during PS scrambling and demonstrated that while other non-ATP-dependent lipid transporters with similar architecture transport lipid following a "trap-and-flip" mechanism, hSERINC3 adopts a "credit card" mechanism of lipid sc2025-01-01T00:00:00Z2025 Nov2026-06-13T03:15:03.194Z2026-06-13T03:08:56.693ZS-EPMC126426334129292510.1101/2025.11.13.688349