ADDP and PS-PPh3: an efficient Mitsunobu protocol for the preparation of pyridine ether PPAR agonists.

A series of pyridine ether PPAR agonists were synthesized through an ADDP and PS-PPh3 modified Mitsunobu protocol, which eliminated significant by-product formation. This method proved to be versatile, efficient and amenable to parallel synthesis.

Protein conformational transitions coupled to binding in molecular recognition of unstructured proteins: hierarchy of structural loss from all-atom Monte Carlo simulations of p27Kip1 unfolding-unbinding and structural determinants of the binding mechanism.

Conformational transitions coupled to binding are studied for the p27(Kip1) protein which undergoes a functional disorder-to-order folding transition during tertiary complex formation with the phosphorylated cyclin A-cyclin-dependent kinase 2 (Cdk2) binary complex. Temperature-induced Monte Carlo simulations of p27(Kip1) unfolding-unbinding carried out from the crystal structure of the tertiary complex have revealed a systematic trend in the hierarchy of structural loss for p27(Kip1) and a considerable difference in mobility of p27(Kip1) secondary structure elements. The most persistent interactions of p27(Kip1) at the intermolecular interface during unfolding-unbinding simulations are formed by beta-hairpin and beta-strand that on average maintain their structural integrity considerably longer than other p27(Kip1) elements.