biostudies-literatureZelnik IDIsrael Science Foundation1. The Dr. Barry Sherman Institute for Medicinal Chemistry. 2. A donation in memory of Sam Switzer.Minerva FoundationThe Walt and Rowena Shaw Foundation.2330https://www.ebi.ac.uk/biostudies/studies/S-EPMC10122649biostudies-literatureUnknown14(1)Until now, membrane-protein stabilization has relied on iterations of mutations and screening. We now validate a one-step algorithm, mPROSS, for stabilizing membrane proteins directly from an AlphaFold2 model structure. Applied to the lipid-generating enzyme, ceramide synthase, 37 designed mutations lead to a more stable form of human CerS2. Together with molecular dynamics simulations, we propose a pathway by which substrates might be delivered to the ceramide synthases.Nature communicationsComputational design and molecular dynamics simulations suggest the mode of substrate binding in ceramide synthases.PMC1012264918441466/19Dingjan TWeinstein JJZelnik IDMestre BBen-Dor SFuterman AHIzrailov SFleishman SJfalseComputational design and molecular dynamics simulations suggest the mode of substrate binding in ceramide synthases.Until now, membrane-protein stabilization has relied on iterations of mutations and screening. We now validate a one-step algorithm, mPROSS, for stabilizing membrane proteins directly from an AlphaFold2 model structure. Applied to the lipid-generating enzyme, ceramide synthase, 37 designed mutations lead to a more stable form of human CerS2. Together with molecular dynamics simulations, we propose a pathway by which substrates might be delivered to the ceramide synthases.2023-01-01T00:00:00Z2023 Apr2026-05-29T02:24:20.916Z2025-02-19T04:16:00.055ZS-EPMC101226493708750010.1038/s41467-023-38047-x