The Solid-State Terahertz Spectrum of MDMA (Ecstasy) – A Unique Test for Molecular Modeling Assignments

In press, in Chemical Physics Letters (CPL).  Yes, the blog has taken a bit of a turn, from high explosives to illicit drugs.  I expect my google rating to rise sharply with this post.  The protonated form of the 3,4-methylene-dioxymethamphetamine (Ecstasy, but I’ll keep the post legit, so it is herein referred to as MDMA) molecule (herein referred to as MDMA:H+) and MDMA:H+ in its crystal cell with a chloride ion (Cl, the crystal form herein referred to as MDMA:HCl) is shown below in yet another fantastic NanoEngineer-1 rendering (if I do say so myself).

This CPL article is, to some extent, a response to those in the terahertz community who continue to attempt spectral assignments of crystalline and poly-crystalline samples using isolated-molecule quantum chemical calculations.  The MDMA:HCl sample and MDMA molecule, as a pair, are a very interesting case study of theory and experiment for reasons detailed below.  The spectra, shown below from a previous version of the paper (but the same spectra), show quite a bit of detail that will make sense shortly.

Panel A shows the isolated-molecule calculation for the neutral MDMA molecule at a B3LYP/6-31G(d) level of theory (in red).  You will note that this simulated spectrum is in very good agreement with experiment (in black), reproducing all of the major features and showing a number of smaller features that account for shoulders.  This agreement was the basis for the assignment of the MDMA:HCl spectrum reported in: G Wang, J Shen, Y Jia. “Vibrational spectra of ketamine hydrochloride and 3,4-methylenedioxymethamphetamine in terahertz range.” Journal of Applied Physics 102 (2007) 013106/1-06/4.

The new theoretical analysis reported in the CPL article was instigated by this assignment in this previous publication.  Relevant to the measured sample and the previously reported assignment, two points arise that require address.

1. The previous calculation, as reported, was of the neutral MDMA molecule and is reasonably close to the MDMA spectrum shown above (in red.  This calculation was redone for the CPL article for comparative purposes).  As the experimental THz sample was of solid-state MDMA:HCl, the appropriate form of the molecule to run is not the neutral MDMA molecule, but the protonated form, MDMA:H+.  The protonated form has a different vibrational spectrum (shown in green in Panel A) than the isolated molecule form.  At the very least, the isolated-molecule to consider for the MDMA:HCl sample must be the protonated form.  Interestingly, the re-calculation at B3LYP/6-31G(d) reported for the CPL article predicts a fifth vibrational mode at 48.0 cm-1 that was not reported in the previous study.  We do not know if the previous group missed that peak in the write-up, decided that (since it is a low-intensity mode) it was not worth reporting, or if their starting molecular geometry was somehow different so that the other four modes were predicted to be in the same region and this mode was somehow turned off.

2. The solid-state spectrum shown in Panel B at a BP/DNP level of theory does not agree as well as the isolated-molecule MDMA B3LYP/6-31G(d) calculation. That being said, THAT IS NOT THE POINT.  The goal of a simulated spectrum IS NOT to obtain the closest spectral agreement with experiment.  The goal IS to explain the solid-state spectrum with the best theoretical model possible that, hopefully, is as close to the experimental result as possible.  In this case, the solid-state BP/DNP spectrum contains a finite number of vibrational modes that do group according to features in the THz spectrum, making the assignment reasonably straightforward.  Interestingly, the two most intense modes in the solid-state BP/DNP calculations involve the motions of the Cl…H+-N chains, which CANNOT be accounted for in an isolated-molecule calculation of either the neutral MDMA molecule or the protonated MDMA:H+.

In summary, as taken from the CPL paper:

With all of these considerations taken into account in this re-examination of the MDMA.HCl THz spectrum, it is found that this system serves as a fortuitous example of one whose THz spectrum is predicted quite precisely by two very different approaches, but is only described accurately by one that considers the crystal environment and the actual state of the molecule in its solid-state form.

Damian G. Allis1,2, Patrick M. Hakey1, and Timothy M. Korter1

1. Department of Chemistry, Syracuse University, Syracuse NY 13244-4100 USA
2. Nanorex, Inc., P.O. Box 7188, Bloomfield Hills, MI 48302-7188 USA

Abstract: The terahertz (THz, far-infrared) spectrum of 3,4-methylene-dioxymethamphetamine hydrochloride (Ecstasy) is simulated using solid-state density functional theory.  While a previously reported isolated-molecule calculation is noteworthy for the precision of its solid-state THz reproduction, the solid-state calculation predicts that the isolated-molecule modes account for only half of the spectral features in the THz region, with the remaining structure arising from lattice vibrations that cannot be predicted without solid-state molecular modeling.  The molecular origins of the internal mode contributions to the solid-state THz spectrum, as well as the proper consideration of the protonation state of the molecule, are also considered.

www.sciencedirect.com/science/journal/00092614
en.wikipedia.org/wiki/Explosive
en.wikipedia.org/wiki/Recreational_drug_use
www.google.com
en.wikipedia.org/wiki/Methylenedioxymethamphetamine
en.wikipedia.org/wiki/Chloride
www.nanorex.com
en.wikipedia.org/wiki/Terahertz
www.thznetwork.org/wordpress
en.wikipedia.org/wiki/Quantum_chemistry
en.wikipedia.org/wiki/Hybrid_functional
en.wikipedia.org/wiki/Basis_set_%28chemistry%29
scitation.aip.org/journals/doc/JAPIAU-ft/vol_102/iss_1/013106_1.html
jap.aip.org/jap/top.jsp
en.wikipedia.org/wiki/Protonation
en.wikipedia.org/wiki/Density_functional_theory
www.somewhereville.com
chemistry.syr.edu/faculty/korter.html
chemistry.syr.edu
www.syr.edu

Oral Insulin Delivery Cover Image (And Associated Syracuse Research Article) in ChemMedChem

You’ve heard about it, you’ve read about it, you’ve seen it on color TV, you’ve even seen it streamed. The cover story in this month’s issue of ChemMedChem is a communication by members and collaborators of the Robert Doyle Group here at Syracuse University. The report describes the B12/TCII-based uptake of insulin, a process that occurs via the ingestion of a B12-insulin conjugate. In case you missed that, the delivery is oral, not by needle. For those of us that pass out at anything needle-related at about the time that the alcohol wipe is opened, that’s a positive step forward for getting rid of any syringe-related medicine altogether.

full image

With the cover story comes the cover image shown above, a structure calculation on the insulin-B12/TCII complex. The bases for this structure can be found in the Protein Data Bank, including the TCII-B12 complex reported in PDB entry 2BB5 (the only hack in the structure calculation involved the replacement of the cobalt for iron to use already available bond parameters) and the insulin structure reported in PDB entry 1ZNI. The covalent attachment of the insulin to B12 can be found in the article. Structure manipulation was performed with a combination of NanoEngineer-1 and VMD, VMD being included in the mix in order to generate the ribbon renderings of the insulin and TCII protein backbones. As for the accuracy of the calculation, time and a synchrotron X-ray source will tell.

For much more information and numerous links to new stories related to the research in the article, I direct you to the group website of Robert Doyle and the various links to news stories available in his departmental publication list.

chemmedchem cover
From ChemMedChem. Click HERE to go to the article.

From the website:

Cover Picture: Vitamin B12 as a Carrier for the Oral Delivery of Insulin (ChemMedChem 12/2007). The cover picture shows an orally active, glucose-lowering vitamin B12-insulin conjugate bound to the B12 uptake protein transcobalamin II (TCII). The inset shows a close-up view of the TCII binding pocket. (Insulin is in red; vitamin B12 is in bright yellow.) For details, see the Communication by T. J. Fairchild, R. P. Doyle, et al. on p. 1717 ff.

www3.interscience.wiley.com/journal/110485305/home
chemistry.syr.edu/faculty/doyle.html
www.syr.edu
www3.interscience.wiley.com/cgi-bin/abstract/117354616/ABSTRACT?CRETRY=1&SRETRY=0
en.wikipedia.org/wiki/B12
en.wikipedia.org/wiki/Insulin
en.wikipedia.org/wiki/Transcobalamin
www3.interscience.wiley.com/journal/117354609/graphissue
www.rcsb.org/pdb
www.rcsb.org/pdb/explore.do?structureId=2BB5
www.rcsb.org/pdb/explore.do?structureId=1ZNI
www.nanorex.com
www.ks.uiuc.edu/Research/vmd
en.wikipedia.org/wiki/Synchrotron
chemistry.syr.edu/faculty/doyle_group/index.html
chemistry.syr.edu/faculty/doyle.html#pubs

POV-Ray The Error Number Is -199 Potential Remedy For OSX

This post provides a possible fix for an OSX POV-Ray error with precious little information available about it anywhere online. The error,

The Error number is -199. (For internal reference only!)

appears upon startup and exits from the program proper, such that POV-Ray becomes useless (not pleasant when you need that last minute image 30 seconds before lecturing).

POVRay

The only mention online (if you search by the message text) can be found at

http://news.povray.org/povray.macintosh/thread/%3Cweb.431de75539863b47bd78a280@news.povray.org%3E/

The error itself is not diagnosed, only noting that a corrupted file is not being accessed upon startup and that running a Disk Utility verification/fixing and reinstalling POV-Ray solves the problem. If this has happened to you, you may have noted that verification/fixing and re-installation does not do the trick.

The origin of the problem on my machine could be traced to a crashed POV-Ray rendering run of a number of images and the retention of the file POV-Ray Mac 3.6.plist in my /[USER]/Library/Preferences/ directory, which typically only contains the file POV-Ray Preferences 3.5 (why an installation of POV-Ray 3.6 would still leave a 3.5 Preference file is beyond the scope of this post).

Deleting the POV-Ray Mac 3.6.plist file fixes the problem.

www.apple.com
www.povray.org
news.povray.org/povray.macintosh/thread/%3Cweb.431de75539863b47bd78a280@news.povray.org%3E