Solution Structure And Constrained Molecular Dynamics Study Of Vitamin B12 Conjugates Of The Anorectic Peptide PYY(3-36)

#50, published in ChemMedChem (11 (2016), 9, 1015-1020), DOI:cmdc.201600073.

The key to molecular dynamics simulations is recycling – specifically, going into a first project with enough organization to know how to use everything in the next study. While that first successful connectivity table, parameter assignment, and RESP charge generation for something as Frankenstein-esque as vitamin B12 is the north face of Everest, that next simulation is simply a matter of having atom codes in your PDB file standardized.

And, speaking of PDBs, article #50 has the added bonus of having its own entry in the Protein Databank as 2NA5 – quite a treat (to me, anyway).

And furthermore, this is the first of my publications to benefit from the Research Computing infrastructure on the Syracuse University campus – the throughput of calculations for future work is completely unprecedented in my history of resource access anywhere (the drop in storage prices is very real to some of us).

2016oct5_fig_4_b12_pyy_front_v2

Authors: Henry K.E., Kerwood D.J., Allis D.G., Workinger J.L., Bonaccorso R.L., Holz G.G., Roth C.L., Zubieta J., and Doyle R.P.

Abstract: Vitamin B12-peptide conjugates have considerable therapeutic potential through improved pharmacokinetic and/or pharmacodynamic properties imparted on the peptide upon covalent attachment to vitamin B12 (B12). There remains a lack of structural studies investigating the effects of B12 conjugation on peptide secondary structure. Determining the solution structure of a B12-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 B12 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 B12 conjugates and validates the fact that B12 can be conjugated to a peptide without markedly affecting peptide secondary structure.

ChemMedChem Cover For April 2013 – Treating Type II Diabetes Through B12 Conjugation

The back cover picture shows two views at 150 degree rotation of vitamin B12 conjugated to the potent anti- hyperglycemia peptide glucagon-like peptide-1 (GLP-1). The conjugate displays similar receptor binding and agonism to unconjugated GLP-1, including insulin potentiation from human transplant pancreatic islet cells, which bodes well for oral delivery of GLP-1 through the B12 dietary pathway. For more details, see the Communication by Robert P. Doyle et al. on p. 582 ff.

From the free press department… The cover for the April, 2013 issue of ChemMEDChem (just the cover art this time, no theoretical content in the associated article. All the theory's figured out!). I'm still awaiting the journal's posting of the article content but wanted to get something up in March. For related content, see the discussion on the "MedChemComm September 2012 Front Cover Image For The 'Examining The Effects Of Vitamin B12 Conjugation…' Paper" post or any of the B12-related posts on this site (www.somewhereville.com/index.php?s=b12). This work is similar in scope to the B12-insulin bioconjugate work in the previous studies, but now includes a different peptide (glucagon-like peptide-1) with similar properties.