TY - JOUR
T1 - Conformational investigation of the structure-activity relationship of GdFFD and its analogues on an achatin-like neuropeptide receptor of
T2 - Aplysia californica involved in the feeding circuit
AU - Do, Thanh D.
AU - Checco, James W.
AU - Tro, Michael
AU - Shea, Joan Emma
AU - Bowers, Michael T.
AU - Sweedler, Jonathan V.
N1 - Funding Information:
We gratefully acknowledge support from the National Institutes of Health, Award No. P30 DA018310 from the National Institute on Drug Abuse and Award No. R01 NS031609 from the National Institute of Neurological Disorders and Stroke (both to J. V. S.), and the National Science Foundation, Award No. CHE-1565941 (M. T. B.) and MCB-1716956 (J.-E. S.). This work used the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation grant number OCI-1053575. The authors acknowledge the Texas Advanced Computing Center (TACC) at The University of Texas at Austin for providing HPC resources through the XSEDE grant number TG-CHE150069 (J. V. S.) and TG-MCA05S027 (J.-E. S.). We acknowledge support from the Center for Scientific Computing at the CNSI and MRL at the University of California at Santa Barbara: an NSF MRSEC (DMR-1121053) and NSF CNS-0960316. J. W. C. was supported in part by a Beckman Institute Postdoctoral Fellowship, funded by a Beckman Foundation gift to the Beckman Institute for Advanced Science and Technology at the University of Illinois at Urbana-Champaign. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.
Publisher Copyright:
© 2018 the Owner Societies.
PY - 2018
Y1 - 2018
N2 - Proteins and peptides in nature are almost exclusively made from l-amino acids, and this is even more absolute in the metazoan. With the advent of modern bioanalytical techniques, however, previously unappreciated roles for d-amino acids in biological processes have been revealed. Over 30 d-amino acid containing peptides (DAACPs) have been discovered in animals where at least one l-residue has been isomerized to the d-form via an enzyme-catalyzed process. In Aplysia californica, GdFFD and GdYFD (the lower-case letter "d" indicates a d-amino acid residue) modulate the feeding behavior by activating the Aplysia achatin-like neuropeptide receptor (apALNR). However, little is known about how the three-dimensional conformation of DAACPs influences activity at the receptor, and the role that d-residues play in these peptide conformations. Here, we use a combination of computational modeling, drift-tube ion-mobility mass spectrometry, and receptor activation assays to create a simple model that predicts bioactivities for a series of GdFFD analogs. Our results suggest that the active conformations of GdFFD and GdYFD are similar to their lowest energy conformations in solution. Our model helps connect the predicted structures of GdFFD analogs to their activities, and highlights a steric effect on peptide activity at position 1 on the GdFFD receptor apALNR. Overall, these methods allow us to understand ligand-receptor interactions in the absence of high-resolution structural data.
AB - Proteins and peptides in nature are almost exclusively made from l-amino acids, and this is even more absolute in the metazoan. With the advent of modern bioanalytical techniques, however, previously unappreciated roles for d-amino acids in biological processes have been revealed. Over 30 d-amino acid containing peptides (DAACPs) have been discovered in animals where at least one l-residue has been isomerized to the d-form via an enzyme-catalyzed process. In Aplysia californica, GdFFD and GdYFD (the lower-case letter "d" indicates a d-amino acid residue) modulate the feeding behavior by activating the Aplysia achatin-like neuropeptide receptor (apALNR). However, little is known about how the three-dimensional conformation of DAACPs influences activity at the receptor, and the role that d-residues play in these peptide conformations. Here, we use a combination of computational modeling, drift-tube ion-mobility mass spectrometry, and receptor activation assays to create a simple model that predicts bioactivities for a series of GdFFD analogs. Our results suggest that the active conformations of GdFFD and GdYFD are similar to their lowest energy conformations in solution. Our model helps connect the predicted structures of GdFFD analogs to their activities, and highlights a steric effect on peptide activity at position 1 on the GdFFD receptor apALNR. Overall, these methods allow us to understand ligand-receptor interactions in the absence of high-resolution structural data.
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U2 - 10.1039/c8cp03661f
DO - 10.1039/c8cp03661f
M3 - Article
C2 - 30112548
AN - SCOPUS:85052846538
SN - 1463-9076
VL - 20
SP - 22047
EP - 22057
JO - Physical Chemistry Chemical Physics
JF - Physical Chemistry Chemical Physics
IS - 34
ER -