Dynamique structurale du récepteur nucléaire PPARgamma

PPARgamma is a regulator of lipid metabolism and is implicated in many different physiological and pathological processes. It acts as an allosteric hub receiving chemical signals that are then translated into biological responses. This action depends on changes in its conformation and its structural dynamics, the latter being difficult to quantify. An atomic level understanding of the molecular mechanisms PPARgamma activity can be understood by studying the underlying structural dynamics, particularly those of collective motions. We developed an integrated approach to study low frequency collective structural dynamics of proteins. It is a combined far infrared spectroscopy – molecular dynamics simulation approach called “Ensemble Averaged Normal Modes”. This allowed us to characterize protein fluctuations, computed IR spectra, and correlated motions. Developed protocol was applied to PPARgamma ligand-binding domain, in apo and holo forms (bound to agonist ligand GW1929) and two cancer-associated mutants (T4757M and F310S). Collective motions of PPARgamma were further studied through simulations incorporating polarization effects.