Inter-leaflet coupling is critical to control the dynamics of membrane domain registration/anti-registration, which is important in maintaining proper biological functions. Factors such as lipid acyl chain inter-digitation and membrane remodeling have been found to be able to regulate the inter-leaflet coupling. However, detailed molecular mechanisms that dominate the inter-leaflet coupling are still far from clear. Here, we revealed that lipid acyl chain cis double bond position can regulate the inter-leaflet coupling according to our coarse-grained and all-atom molecular dynamics simulations. The farther the double bond is away from the lipid tail terminal, the weaker the inter-leaflet attractive interactions between unsaturated lipids. Therefore, the relative motions of membrane domains in two membrane leaflets become more obvious (membrane domain anti-registration). Generally, our simulations validated a direct indicator for the inter-leaflet coupling strength, which provides physical insights into the molecular mechanisms of membrane domain registration/anti-registration.