Structural dynamics of neuropeptide hPYY

Abstract

We have employed a combination of experiment and simulation to characterize the ensemble of structures sampled by human Peptide YY (hPYY), an important member of the neuropeptide Y family. Experimental structural characterization carried out with far UV circular dichroism spectroscopy and Fourier Transform-Infrared measurements confirmed that the major feature of the secondary structure of hPYY is the α-helix, encompassing about half the peptide residues, with smaller contributions from turn and β-sheet like structures. The peptide undergoes thermal denaturation characterized by a melting temperature of 48°C with an enthalpy change of -24.5 kcal/mol and entropy change of -76.2 cal/(mol K). In our computational studies, based on a 4-μsec MD trajectory generated with the AMBER03 potential, we found excellent agreement of the predicted features with experimental data, including a stable C-terminal helix, a central turn and conservation of about 80% of measured long-range NOE contacts. The main structural fluctuations involved partial helix unwinding and large-scale motions of the N-terminal. Our joint experimental/computational approach leads to several insights into the biological function of PYY. We conclude that the C-terminal helix is crucial for the structural integrity of PYY. The structures and motions found in the simulations suggest microscopic explanations for observed changes in biological activity of the peptide upon mutation and truncation. We also performed microsecond-length MD and replica-exchange simulations of hPYY with the OPLS-AA force field, for which computed structures did not agree well with experimental data, predicting significant loss of helicity and NOE contacts.

Mesoporous Silicon (PSi) for Sustained Peptide Delivery: Effect of PSi Microparticle Surface Chemistry on Peptide YY3-36 Release

“…Instead, the negligible differences observed with TOPSi may indicate that combined with the better wettability of the material, the peptide is readily desorbed from the surface, while with more hydrophobic THCPSi and UnTHCPSi PYY3-36 may be oriented towards the surface of the PSi according to its hydrophobic segments. The carboxylic acid terminated UnTHCPSi surface additionally indicates slightly stronger conformational changes than THCPSi, as the α-helix structure and random conformation related peaks at 1654 cm -1 and 1641 cm -1 become more pronounced (44). The presence of possible hydrogen bonding between the surface carboxyl groups and the peptide amine groups cannot be excluded, as both the amide I band and the adjacent carbonyl peak at 1715 cm -1 overlap considerably.…”

Periodontal-induced chronic inflammation triggers macrophage secretion of Ccl12 to inhibit fibroblast-mediated cardiac wound healing

“…The differences in protein sequence resulted in structural changes in mCcl2 that are absent in mCcl12 and hMCP-1 ( Figure 8B). While sequence homology is high for both isoforms, hMCP-1 and mCcl12 contain a β-strand at residue 20 that is absent in mCcl2, resulting in changes in binding efficiency and, thus, protein function (32)(33)(34). Mouse Ccl12, therefore, is closer in homology and structure to hMCP-1.…”

Peptide hormones and lipopeptides: from self‐assembly to therapeutic applications

“…The results indicated an α ‐helical structure due to a maximum near 190 nm and two minima near 208 and 222 nm. A minimum near 200 nm was also observed, which corresponds to a random‐coil structure (Figure 8) 82.…”

“…The Y 2 receptors are located in Figure 8. Temperature dependant CD spectra of human PYY in 20 mM acetate buffer at pH 4.6 [82]. the hippocampus, sympathetic and parasympathetic nerve fibres, intestines and certain blood vessels and have been implicated in regulating food intake and gastric emptying [88].…”