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Solution Structure and Constrained Molecular Dynamics Study of Vitamin B 12 Conjugates of the Anorectic Peptide PYY(3–36)
Author(s) -
Henry Kelly E.,
Kerwood Deborah J.,
Allis Damian G.,
Workinger Jayme L.,
Bonaccorso Ron L.,
Holz George G.,
Roth Christian L.,
Zubieta Jon,
Doyle Robert P.
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600073
Subject(s) - conjugate , peptide , chemistry , tetrapeptide , molecular dynamics , vitamin b12 , biochemistry , computational chemistry , mathematical analysis , mathematics
Vitamin B 12 –peptide conjugates have considerable therapeutic potential through improved pharmacokinetic and/or pharmacodynamic properties imparted on the peptide upon covalent attachment to vitamin B 12 (B 12 ). There remains a lack of structural studies investigating the effects of B 12 conjugation on peptide secondary structure. Determining the solution structure of a B 12 –peptide conjugate or conjugates and measuring functions of the conjugate(s) at the target peptide receptor may offer considerable insight concerning the future design of fully optimized conjugates. This methodology is especially useful in tandem with constrained molecular dynamics (MD) studies, such that predictions may be made about conjugates not yet synthesized. Focusing on two B 12 conjugates of the anorectic peptide PYY(3–36), one of which was previously demonstrated to have improved food intake reduction compared with PYY(3–36), we performed NMR structural analyses and used the information to conduct MD simulations. The study provides rare structural insight into vitamin B 12 conjugates and validates the fact that B 12 can be conjugated to a peptide without markedly affecting peptide secondary structure.