Computational design and molecular dynamics simulations suggest the mode of substrate binding in ceramide synthases
Iris D. Zelnik, Beatriz Mestre, Jonathan J. Weinstein, Tamir Dingjan, Stav Izrailov, Shifra Ben‐Dor, Sarel J. Fleishman, Anthony H. Futerman
Abstract
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.
Topics & Concepts
CeramideMolecular dynamicsSphingolipidCeramide synthaseEnzymeSubstrate (aquarium)ChemistryDynamics (music)Lipid signalingBiophysicsBiochemistryCell biologyComputational biologyBiologyPhysicsComputational chemistryApoptosisEcologyAcousticsSphingolipid Metabolism and SignalingLipid Membrane Structure and BehaviorLipid metabolism and biosynthesis