The animal nervous system employs chemical neurotransmitters to relay messages from one neuron to the next. We focused our interest on a family of neurotransmitters called FMRFamide-like (or FLP) neuropeptides. FLPs are particularly interesting because they are involved in a wide range of neural functions, including learning, feeding processes, and pain modulation.

In the first part of our study, the different potencies of two FLPs against neuropeptide receptor 1 (NPR-1) in the nematode Caenorhabditis elegans were evaluated. DFDGAMPGVLRF-NH₂ and EMPGVLRF-NH ₂ exhibit different activities against NPR-1, with the longer peptide presenting a lower potency. Replica-Exchange Molecular Dynamics (REMD) simulations suggested that DFDGAMPGVLRF-NH₂ adopts mainly two conformations, forming either a C-terminal loop, or a bicyclic structure involving N-terminal with C-terminal-loop interactions. Conversely, EMPGVLRF-NH₂ presents one dominant conformation, with the PGVLRF-NH₂ region resembling the corresponding region of DFDGAMPGVLRF-NH₂. Furthermore, it was concluded that when the N-terminal-associated interactions are eliminated, the activity of the peptide is enhanced, whereas the PGVLRF-NH₂ motif is a unique conformation. These findings suggest that the N-terminal region behaves independently and is determinant for the differences in binding affinity.

In the second part of our study, a mammalian neuropeptide involved in pain modulation was considered. REMD methodology was applied to identify structural characteristics associated with the high binding affinity of NPFF (FLFQPQRF-NH ₂) for a specific receptor. Backbone conformations dictated by interactions among Gln4 and the C-terminal Arg and Phe residues, are necessary for high affinity. However, these interactions alone are not sufficient for binding to the receptor; we observed that the C-terminal–Gln4 interactions enable appropriate positioning for the side chains of Phe and Arg. A free and solvent-exposed aromatic ring, along with an oriented (and positively charged) arginine side chain, are possibly the main structural units that recognize receptor binding sites.

These studies provide further insight concerning structural characteristics of FLPs that are critical for binding to receptors in the animal nervous system. Although the structure-activity relationship of FLPs remains elusive, the outcomes of this investigation shed new light into this area, and will hopefully be a stepping stone towards the understanding of the pharmacological effects of FLPs.