Estudio computacional de proteínas transportadoras de lípidos inmunológicamente relevantes y de su interacción con ligandos unidos a membranas

Allergic diseases are an increasing concern, yet, unfortunately, most of the molecular events that lead to an immune response against an innocuous protein (“allergen”) still remain unknown. Thus, efforts are being made to elucidate why a protein becomes an allergen. In this regard, a significant proportion of known allergen proteins are lipid transfer proteins (LTPs) and recent compelling evidence suggests that their lipidic ligands might play a significant role in the sensitization phase of allergy. Of special interest is Pru p 3, a LTP from peach fruit and model in food allergy, whose natural lipidic ligand was recently identified. Experiments have demonstrated the presence of the ligand inside CD1d receptors that in turn present lipidic antigens to T-cells triggering immune responses. Moreover, the most important type of proteins that assist in lipid trafficking in the human immune system are also LTPs called saposins. Interestingly, Pru p 3 has a similar fold and size to saposins and even a significant structural relationship with one type of these proteins (saposin A). Based on these similarities, a computational study aimed to analyze the dynamic properties of both Pru p 3 and two relevant saposins (A and B) in their interactions with lipid ligands and with membranes is presented in this TFG. Molecular dynamics (MD) simulations at all-atom and coarse grained resolution, biased MD to obtain energy landscapes, calculation of protonation states and of Poisson-Boltzmann electrostatic potentials are combined to get a detailed view of these interactions. The results show that, in contrast to Pru p 3, saposins display changes in structure, aggregation state and pH-dependence to perform their function. MD calculations also provide a common binding mechanism to membranes of these LTPs and reveal a preferred binding of Pru p 3 to anionic instead of neutral phospholipids. Additional computational protocols developed to further investigate protein-lipid ligands-membrane systems of immunological interest are finally presented