Molecular dynamics of NPYY1 receptor activation

A three-dimensional model of the human neuropeptide Y(NPY)Y-1 receptor (hY( 1)) was constructed, energy refined and used to simulate molecular receptor interactions of the peptide ligands NPY, [L31, P34]NPY, peptide YY (PYY) a nd pancreatic polypeptide (PP), and of the nonpeptide antagonist R-N-2-(dip henylacetyl)-N-(4-hydroxyphenyl)methyl-argininamide (BIBP3226) and its S-en antiomer BIBP3435. The best complementarity in charges between the receptor and the peptides, and the best structural accordance with experimental stu dies, was obtained with amino acid 1-4 of the peptides interacting with Asp 194, Asp200, Gln201, Phe202 and Trp288 in the receptor. Arg33 and Arg35 of the peptides formed salt bridges with Asp104 and Asp287, respectively, whil e Tyr36 interacted in a binding pocket formed by Phe41, Thr42, Tyr100, Asn2 97, His298 and Phe302. Calculated electrostatic potentials around NPY and h Y(1) molecules indicated that ligand binding is initiated by electrostatic interactions between a highly positive region in the N- and C-terminal part s of the peptides, and a negative region in the extracellular receptor doma ins. Molecular dynamics simulations of NPY and BIBP3226 interactions with t he receptor indicated rigid body motions of TMH5 and TMH6 upon NPY binding as mechanisms of receptor activation, and that BIBP3226 may act as an antag onist by constraining these motions. (C) 1999 Elsevier Science Ltd. All rig hts reserved.