Differential dynamics of the serotonin1A receptor in membrane bilayers of varying cholesterol content revealed by all atom molecular dynamics simulation.
The serotonin1A 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 serotonin1A 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 serotonin1A receptor. Our results show that the presence of physiologically relevant concentration of membrane cholesterol alters conformational dynamics of the serotonin1A 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.
a Center for Condensed Matter Theory, Department of Physics, Indian Institute of Science , Bangalore , India .|b Department of Chemistry , RV College of Engineering , Bangalore , India .
Swarna M
SM
Patra
a Center for Condensed Matter Theory, Department of Physics, Indian Institute of Science , Bangalore , India .
Sudip
S
Chakraborty
c CSIR-National Chemical Laboratory , Pune , India , and.
Ganesh
G
Shahane
c CSIR-National Chemical Laboratory , Pune , India , and.
Xavier
X
Prasanna
c CSIR-National Chemical Laboratory , Pune , India , and.
Durba
D
Sengupta
a Center for Condensed Matter Theory, Department of Physics, Indian Institute of Science , Bangalore , India .
Prabal K
PK
Maiti
d CSIR - Centre for Cellular and Molecular Biology , Hyderabad , India.
Amitabha
A
Chattopadhyay
D001665:Binding Sites; D002462:Cell Membrane / Q000737:chemistry* / Q000378:metabolism; D002784:Cholesterol / Q000737:chemistry* / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
D008055:Lipids; D043562:Receptors, G-Protein-Coupled; D044282:Receptor, Serotonin, 5-HT1A; D002784:Cholesterol
GPCR; membrane cholesterol; molecular dynamics simulation; serotonin1A receptor