2 research outputs found
Estimating the Lipophobic Contributions in Model Membranes
The
insertion and association of membrane proteins is critical
in several cellular processes. These processes were thought to be
protein-driven, but increasing evidence points toward an important
role of the lipid bilayer. The lipid-mediated contribution has been
shown to be important in the association of membrane peptides, but
the corresponding “lipophobic” component has not been
directly estimated. Here, we calculate the free energy of insertion
for transmembrane peptides and estimate the lipophobic component from
the cost of cavity formation. The free-energy calculations were performed
using the coarse-grain Martini force field, which has been successful
in predicting membrane protein interactions. As expected, the charged
moieties have the least favorable free energy of insertion and the
highest cost of cavity formation. A length dependence was observed
in polyalanine peptides with the lipid-mediated component increasing
nonlinearly with peptide length. Membrane fluidity was tested by varying
the temperature, and opposing effects were observed for short and
long peptides. The dependence of the lipid-mediated effects on peptide
length and temperature was not uniform and gives valuable insight
into the anisotropic nature of the membrane. The results are an important
step in estimating membrane effects in protein insertion and association
Differential dynamics of the serotonin<sub>1A</sub> receptor in membrane bilayers of varying cholesterol content revealed by all atom molecular dynamics simulation
<p>The serotonin<sub>1A</sub> receptor belongs to the superfamily of G protein-coupled receptors (GPCRs) and is a potential drug target in neuropsychiatric disorders. The receptor has been shown to require membrane cholesterol for its organization, dynamics and function. Although recent work suggests a close interaction of cholesterol with the receptor, the structural integrity of the serotonin<sub>1A</sub> receptor in the presence of cholesterol has not been explored. In this work, we have carried out all atom molecular dynamics simulations, totaling to 3 μs, to analyze the effect of cholesterol on the structure and dynamics of the serotonin<sub>1A</sub> receptor. Our results show that the presence of physiologically relevant concentration of membrane cholesterol alters conformational dynamics of the serotonin<sub>1A</sub> receptor and, on an average lowers conformational fluctuations. Our results show that, in general, transmembrane helix VII is most affected by the absence of membrane cholesterol. These results are in overall agreement with experimental data showing enhancement of GPCR stability in the presence of membrane cholesterol. Our results constitute a molecular level understanding of GPCR-cholesterol interaction, and represent an important step in our overall understanding of GPCR function in health and disease.</p