Analysis of structure-function relationships of neuropeptide Y using molecular dynamics simulations and pharmacological activity and binding measurements.

Studies on the structure-function relationship of neuropeptide Y (NPY) were undertaken using a combination of in vacuo molecular dynamics (MD) simulations and pharmacological receptor binding and biological activity measurements. Following a conformational search of NPY from which a theoretical structure was determined, a study of the structural and dynamic changes in the region of amino acids 25-36 was performed in a variety of NPY fragments and in the NPY free acid. Results revealed an increased structural change as the fragment size was decreased. Also, the mobility appears to be lowest in the full NPY vs the NPY fragments. Pharmacological measurements showed a decreased receptor binding and biological activity as fragment size decreased. Combination of the two approaches suggests a model where conformational maintenance and low configurational entropy of the 25-36 region of NPY favors both receptor binding and biological activity. Furthermore, the possibility of two receptor interaction modes is suggested. Analysis of the NPY structure suggests the direct importance of the amidated C-terminus, Gln34 and His26, an indirect importance of the Tyr1 sidechain as well as the potential importance of an apparent electric 'dipole' in NPY for receptor binding and biological activity.