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Homology and Molecular Dynamics Models of Toll‐Like Receptor 7 Protein and Its Dimerization
Author(s) -
Tseng ChihYuan,
Gajewski Melissa,
Danani Andrea,
Tuszynski Jack A.
Publication year - 2014
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12278
Subject(s) - homology modeling , docking (animal) , transmembrane protein , receptor , g protein coupled receptor , toll like receptor , computational biology , transmembrane domain , innate immune system , dimer , chemistry , protein structure , protein–protein interaction , biology , biochemistry , medicine , enzyme , nursing , organic chemistry
Toll‐like receptor protein 7 is a transmembrane protein playing a crucial role in the signaling pathways involved in innate immunity. Its crystal structure is not yet available, but there are several proteins possessing domains of sufficiently high homology, which enabled us to build a model of the toll‐like receptor protein 7 monomer and gain insights into dimer formation. To obtain a reliable structure prediction, we subjected this model to equilibration using molecular dynamics simulations. Furthermore, the equilibrated monomer structure was used to construct models of dimerization and to predict binding sites for small ligands. Docking studies were performed for some of the known toll‐like receptor protein 7 ligands. We determined that a new homology model generated by the LOOPP server provides a good alternative to a previously reported model. Our docking results indicate that the addition of either imiquimod or 1V209 to a toll‐like receptor protein 7 dimer changes an unfavorable interaction into a favorable one. We found that eight small molecules docked to two pockets in toll‐like receptor protein 7 bind to both pockets at pH 7 and at pH 5.5. This work provides a realistic model that could be used for drug discovery aimed at finding toll‐like receptor protein 7 dimerization activators, with potential clinical applications to a host of diseases, including cancer.