Molecular dynamics simulations of bovine rhodopsin: influence of protonation states and different membrane-mimicking environments

G-protein coupled receptors (GPCRs) are a protein family of outstanding pharmaceutical interest. GPCR homology models, based on the crystal structure of bovine rhodopsin, have been shown to be valuable tools in the drug-design process. The initial model is often refined by molecular dynamics (MD) si...

Full description

Saved in:
Bibliographic Details
Published in:Journal of molecular modeling 2005-12, Vol.12 (1), p.49-64
Main Authors: Schlegel, Birgit, Sippl, Wolfgang, Höltje, Hans-Dieter
Format: Article
Language:English
Subjects:
1,2-Dipalmitoylphosphatidylcholine
Amino Acid Sequence
Animals
Aspartic Acid - chemistry
Carbon Tetrachloride
Cattle
Cell Membrane - chemistry
Cell Membrane - metabolism
Computer Simulation
Glutamic Acid - chemistry
Humans
Hydrogen Bonding
Models, Molecular
Molecular Sequence Data
Protein Structure, Tertiary
Protons
Rhodopsin - chemistry
Rhodopsin - genetics
Rhodopsin - metabolism
Software
Structural Homology, Protein
Water - chemistry
Water - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:G-protein coupled receptors (GPCRs) are a protein family of outstanding pharmaceutical interest. GPCR homology models, based on the crystal structure of bovine rhodopsin, have been shown to be valuable tools in the drug-design process. The initial model is often refined by molecular dynamics (MD) simulations, a procedure that has been recently discussed controversially. We therefore analyzed MD simulations of bovine rhodopsin in order to identify contacts that could serve as constraints in the simulation of homology models. Additionally, the effect of an N-terminal truncation, the nature of the membrane mimic, the influence of varying protonation states of buried residues and the importance of internal water molecules was analyzed. All simulations were carried out using the program-package GROMACS. While N-terminal truncation negatively influenced the overall protein stability, a stable simulation was possible in both solvent environments. As regards the protonation state of titratable sites, the experimental data could be reproduced by the program UHBD (University of Houston Brownian Dynamics), suggesting its application for studying homology models of GPCRs. A high flexibility was observed for internal water molecules at some sites. Finally, interhelical hydrogen-bonding interactions could be derived, which can now serve as constraints in the simulations of GPCR homology models.
ISSN:1610-2940
0948-5023
DOI:10.1007/s00894-005-0004-z