Structure–function relationships of Toll-like receptor domains through homology modelling and molecular dynamics

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Abstract
TLRs (Toll-like receptors) are pattern-recognition receptors of the immune system and recognize pathogens based on distinct molecular signatures. Although different TLRs within the same species (orthologues) or individual TLRs across different species (homologues) are similar in protein sequence, they differ considerably with regard to their function, for example with regard to ligand discrimination or adaptor selection. Owing to the lack of structural information, explanations for these phenomena have been difficult to provide. We have combined homology modelling with energy minimization and Molecular Dynamics simulation in order to address these interesting biological phenomena from a structural angle. Thus three-dimensional models of human and mouse TLR3 and TLR4 domains were successfully generated. Apart from providing a structural framework in which mutagenesis studies (both site-directed and random) can be interpreted and designed, Molecular Dynamics also allowed us to study and simulate protein structure under solution-like conditions. We have applied this approach to the human TLR3 and TLR4 ECDs (ectodomains) providing insights into the dynamics of TLR ECDs. Other conclusions drawn from our structural models are also discussed. We hope that our structural modelling approach, which can be extended to other members of the TLR family or other signal transduction pathways, will serve as a valuable tool for the design of experiments to address questions of TLR biology further.