Multiscale Modeling of the Organization of Receptor Transmembrane Domains in Lipid Membranes




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Membrane proteins have a critical role in signal transduction pathways. The current hypothesis is that different specific arrangements of transmembrane domains (TMD) facilitate the activation mechanism. In this work efficient free energy calculations provide us the favorable arrangements of the growth hormone receptor (GHR) TMDs in lipid membranes. By detail comparison with new experimental data, organizations of the TMDs were linked to activity and a new signaling mechanism is proposed. In a separate effort, we explore the effect of cholesterol on TMD association. Simulations of Glycophorin A (GpA) are conducted in multicomponent bilayers with different cholesterol content. The addition of cholesterol results in changes of the association free energy differences and the interaction interface of TMD dimers. Furthermore, a multiscale method was designed to determine the organization states of GpA TMD with all-atom resolution. Free energy profiles from coarse-grained (CG) and atomistic models were critically compared and found in fair agreement.



Molecular simulations, Transmembrane Protein, Multiscale modeling, Receptors