biostudies-literaturePark SIntramural NIH HHSNational Institutes of HealthNIH HHSNational Science Foundation512-522https://www.ebi.ac.uk/biostudies/studies/S-EPMC10922693biostudies-literatureUnknown45(9)Peptides and proteins play crucial roles in membrane remodeling by inducing spontaneous curvature. However, extracting spontaneous curvatures from simulations of asymmetric bilayers is challenging because differential stress (i.e., the difference of the leaflet surface tensions) arising from leaflet area strains can vary substantially among initial conditions. This study investigates peptide-induced spontaneous curvature δc0p in asymmetric bilayers consisting of a single lipid type and a peptide confined to one leaflet; δc0p is calculated from the Helfrich equation using the first moment of the lateral pressure tensor and an alternative expression using the differential stress. It is shown that differential stress introduced during initial system generation is effectively relaxed by equilibrating using P2₁ periodic boundary conditions, which allows lipids to switch leaflets across cell boundaries and equalize their chemical potentials across leaflets. This procedure leads to robust estimates of δc0p for the systems simulated, and is recommended when equality of chemical potentials between the leaflets is a primary consideration.Journal of computational chemistrySpontaneous curvature generation by peptides in asymmetric bilayers.PMC10922693Z99 HL999999Z01 HL000340MCB‐181069Pastor RWRice AIm WPark SfalseSpontaneous curvature generation by peptides in asymmetric bilayers.Peptides and proteins play crucial roles in membrane remodeling by inducing spontaneous curvature. However, extracting spontaneous curvatures from simulations of asymmetric bilayers is challenging because differential stress (i.e., the difference of the leaflet surface tensions) arising from leaflet area strains can vary substantially among initial conditions. This study investigates peptide-induced spontaneous curvature δc0p in asymmetric bilayers consisting of a single lipid type and a peptide confined to one leaflet; δc0p is calculated from the Helfrich equation using the first moment of the lateral pressure tensor and an alternative expression using the differential stress. It is shown that differential stress introduced during initial system generation is effectively relaxed by equilibrating using P2₁ periodic boundary conditions, which allows lipids to switch leaflets across cell boundaries and equalize their chemical potentials across leaflets. This procedure leads to robust estimates of δc0p for the systems simulated, and is recommended when equality of chemical potentials between the leaflets is a primary consideration.2024-01-01T00:00:00Z2024 Apr2025-07-11T03:04:01.905Z2025-07-11T03:04:01.905ZS-EPMC109226933799128010.1002/jcc.27261