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Published January 22, 2015 | public
Journal Article Open

Disordered Structural Ensembles of Vasopressin and Oxytocin and Their Mutants


Vasopressin and oxytocin are intrinsically disordered cyclic nonapeptides belonging to a family of neurohypophysial hormones. Although unique in their functions, these peptides differ only by two residues and both feature a tocin ring formed by the disulfide bridge between first and sixth cysteine residues. This sequence and structural similarity are experimentally linked to oxytocin agonism at vasopressin receptors and vasopressin antagonism at oxytocin receptors. Yet single- or double-residue mutations in both peptides have been shown to have drastic impacts on their activities at either receptor, and possibly the ability to bind to their neurophysin carrier protein. In this study we perform molecular dynamics simulations of the unbound native and mutant sequences of the oxytocin and vasopressin hormones to characterize their structural ensembles. We classify the subpopulations of these structural ensembles on the basis of the distributions of radius of gyration and secondary structure and hydrogen-bonding features of the canonical tocin ring and disordered tail region. We then relate the structural changes observed in the unbound form of the different hormone sequences to experimental information about peptide receptor binding, and more indirectly, carrier protein binding affinity, receptor activity, and protease degradation. This study supports the hypothesis that the structural characteristics of the unbound form of an IDP can be used to predict structural or functional preferences of its functional bound form.

Additional Information

© 2014 American Chemical Society. Received: June 13, 2014. Revised: September 16, 2014. Publication Date (Web): September 18, 2014. Special Issue: William L. Jorgensen Festschrift. The work reported here is supported by resources of UC Berkeley CITRIS and the National Energy Research Scientific Computing Center, which is supported by the Office of Science of the U.S. Department of Energy under Contract No. DEAC02-05CH11231. T.H.G. thanks the NSF for support under grant CHE-1265731. T.H.G. also acknowledges computational resources obtained under NSF grant CHE-1048789. T.H.G. thanks Bill Jorgensen for his many insightful scientific accomplishments that have proved foundational to the field of molecular simulation.

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August 20, 2023
August 20, 2023