Molecular dynamics simulations of the peroxisome proliferator-activated receptors

The nuclear receptor known as PPAR plays a major role in glucose and fatty acids metabolism, being intimately related to the so-called 'modern diseases' such as obesity and type II diabetes. This work aimed at using molecular dynamics simulations, together with other computational tools, to study structural and dynamics aspects of PPAR at the molecular level, providing new insight into PPAR function. Four specific problems were addressed: i) the study of the concerted motions and the essential dynamics displayed by the recently published structure of an intact NR complex, PPAR/RXR-DNA. This study revealed the existence of long-range mechanical correlations that help to explain allosteric communications. ii) A comparative study to investigate the impact of the oligomeric state on PPAR dynamics and on ligand dissociation pathways. We found that the complexed state favours the formation of salt bridges that are important for ligand dissociation. iii) Investigation of the importance of the ?-pocket for PPAR? activity, in which we shown that ?-pocket occupation by an agonists leads to a strong stabilization of the ?-loop and correlated stabilization of H12. iv) Pharmacophoric modeling of PPAR binding cavity by means of ligands' physical-chemistry properties, which revealed a series of activity-specific sub-cavities that can be used in the future to guide the search for new drugs (AU)