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

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

Receptor tyrosine kinases (RTKs) are a large group of cell-surface receptors which are recognized as essential components of signal transduction pathways for inter and intracellular communication. Almost all RTKs have similar molecular structure, a large extracellular domain (ECD), an intracellular tyrosine kinase domain (ICD) and a single pass transmembrane domain (TMD) connecting the previous two. RTKs act as key regulators of critical cellular processes such as growth, metabolism, differentiation, migration and apoptosis. As a result, either loss-of-function or gain-of-function of individual RTKs can result in carcinogenesis.

Due to the important role in diseases of receptors, their activity should be tightly controlled and regulated. Precise control of the activity of receptors requires molecular engineering of specific components that interfere with the activation mechanism.  Any signals must be transferred through TMDs into intracellular domains and the current hypothesis is that different arrangements of TMDs are most likely critically involved in signaling of receptors by transferring the ICD into active conformation. It has even been proposed that TMDs can act as potential therapeutic targets.

Current experiment methods face challenges in exploring the arrangements of TMDs within a membrane environment. State-of-the-art all atom (AA) simulations face severe temporal and spatial limitations. In this work efficient free energy Monte Carlo (MC) calculations with coarse-grained (CG) models provided us the favorable arrangements of TMDs of the growth hormone receptor (GHR) and the erythropoietin receptor (EPOR) in lipid membranes.  By detailed comparison of GHR TMDs with new intriguing experimental data, two favorable dimer organizations of TMDs were linked to different activity states and a new activation mechanism model for GHR is proposed.

Furthermore, a multiscale method was designed and employed to determine the organization states of TMD with atomistic details. Using the exhaustive sampling offered by the MC coarse-grained simulations we rigorously identified states at distinct separations and assisted by modified rebuilding algorithms we compare free energy profiles calculated at two different resolutions. The multiscale methodology proposed combines the efficiency of the CG model and the accuracy of AA model providing unique insight into the arrangement of TMDs in lipid membranes.

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