Determinação estrutural de TLR1: um estudo de dinâmica molecular e dos polimorfismos associados à proteína

Abstract

During the events of Mycobacterium leprae interaction with host cells, specific genes are activated and are involved in the binding of receptors capable of recognizing patterns, like TLRs (Toll Like Receptors). They modulate autophagy, regulate the formation of lipid vesicles and may lead to cell apoptosis. It has been suggested that subtle variations in genes responsible for immune responses are regulating every step of the host-pathogen interaction. The low genetic variability of M. leprae suggests that host genetic factors may have a major influence on the progression of leprosy. Thus, it is important to know about the TLR1 and TLR2 receptors, which cooperate in the detection of mycobacterial triacylated lipopeptides, and single nucleotide polymorphisms associated with these proteins, to understand the leprosy per se and their reactions. In this context, this study aimed to understand, first of all, how works over time the TLR1 (transmembrane and intracellular domains) complexed with a biological membrane, and analyze the energetic effects of polymorphisms associated, from the sequence of TLR1. Therefore, it was necessary the system structural determination, and performing such analyzes after molecular dynamics. The effects of the mutations were predicted by studies in programs publicly available. The results show the participation of TLR1 alpha-helix transmembrane in a DPPC (dipalmitoylphosphatidylcholine) membrane. Furthermore, analyzes of the molecular dynamics show that the system is stable during the simulation presented in several respects. The effects of polymorphisms reveal that some of them can destabilize the molecule, causing possible changes in susceptibility to leprosy. Therefore, one can conclude that the TLR1 structural model was constructed, as well as the process of molecular dynamics of the system was standardized. Furthermore, the effect of mutations in TLR1 was evaluated as ΔΔG values and, if neutral or deleterious. But, further studies should be performed in order to look for more profound results in assessing the susceptibility of patients with leprosy.