(133b) 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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