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Exploring the Implications of Vitamin B12 Conjugation to Insulin on Insulin Receptor Binding and Cellular Uptake

In press, in the journal ChemMedChem (and, because I think it's hip, I note that the current "obligatory" image for the wikipedia article for ChemMedChem features the image I made for the review article on the topic addressed in this new study). As with many theory papers (there's some experiment in there, too), this very brief article summarizes several months of cyanocobalamin (B12) parameterization and molecular dynamics (MD) simulations. The purpose of the theory was to address all of the major structural snapshots in the uptake process associated with the insulin-B12 bioconjugate being developed as part of the much heralded oral insulin project in Robert Doyle's group here at Syracuse. These structures include:

1. The structure and dynamic properties of the insulin-B12 bioconjugate
2. The binding of B12 to Transcobalamin II (TCII) (for B12 parameterization)
3. The binding of the insulin-B12 bioconjugate to TCII (and the steric demands therein)
4. The interaction of the insulin-B12 bioconjugate, bound to TCII, with the insulin Receptor (IR)

The quantum chemical (for the B12 geometry and missing force constants) and molecular dynamics (GROMACS with the GROMOS96 (53a6)) simulation work is going to serve as the basis for several posts here (eventually) about parameterization, topology generation, and force field development.

As an example of some of the insights modeling provides, the figure above shows the insulin-B12 bioconjugate (the insulin is divided into A and B chains, the A chain in blue and the important division of the insulin B chain in the front half of the rainbow). Insulin is a rather large-scale example of many of the same molecular issues that arise in the analysis of solid-state molecular crystals by either terahertz or inelastic neutron scattering spectroscopy. The packing of molecules in their crystal lattices can lead to significant changes in molecular geometry, be these changes in the stabilization of higher-energy molecular conformations or even deformations in the covalent framework. In the case of insulin, it is found that the crystal geometry (also the geometry of stored insulin in the body) is quite different from the solution-phase form. It's even worse! The B chain end (B20-B30) in the solid-state geometry covers (protects?) the business-end of the insulin binding region to the Insulin Receptor. One can imagine the difficulty in proposing the original binding model for insulin to its receptor from the original crystal data given that the actual binding region is blocked off in the solid-state form! The "Extended" form in the figure is representative of "multiple other" conformations of the B20-B30 region (which mimics the characterized T-state of insulin), those geometries for which the insulin binding region (blue and green) is completely exposed. This extended geometry is also the one that separates the bulk of the insulin structure from the covalently-linked B12 (at Lys29) and, it is argued from the MD simulations in the paper, enables the B12 to still tightly bind to TCII despite the presence of all this steric bulk.

Amanda K. Petrus1, Damian G. Allis1, Robert P. Smith2, Timothy J. Fairchild3 and Robert P. Doyle1

1. Department of Chemistry, Syracuse University, Syracuse, NY 13244, USA
2. Department of Construction Management and Wood Products Engineering, SUNY, College of Environmental Science and Forestry, Syracuse, NY 13210, USA
3. Department of Exercise Science, Syracuse University, Syracuse, NY 13244, USA

Extract: We recently reported a vitamin B12 (B12) based insulin conjugate that produced significantly decreased blood glucose levels in diabetic STZ-rat models. The results of this study posed a fundamental question, namely what implications does B12 conjugation have on insulin's interaction with its receptor? To explore this question we used a combination of molecular dynamics (MD) simulations and immuno-electron microscopy (IEM).

www3.interscience.wiley.com/journal/110485305/home
en.wikipedia.org
en.wikipedia.org/wiki/Chemmedchem
www3.interscience.wiley.com/journal/116323633/abstract
en.wikipedia.org/wiki/Cyanocobalamin
en.wikipedia.org/wiki/Molecular_dynamics
en.wikipedia.org/wiki/Insulin
chemistry.syr.edu/faculty/doyle.html
chemistry.syr.edu/faculty/doyle_group/index.html
www.syr.edu
en.wikipedia.org/wiki/Quantum_chemistry
www.gromacs.org
en.wikipedia.org/wiki/Terahertz
en.wikipedia.org/wiki/Inelastic_neutron_scattering
chemistry.syr.edu
www.syr.edu
www.esf.edu

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Syracuse Astronomical Society President's Message For November, 2008

A repost of the original at the Syracuse Astronomical Society website.

Greetings Fellow Astrophiles!

This is turning into a very orange November newsletter, just in time to remind you of the color that HAD been on the trees just a few weeks ago. The SAS tends to go into hibernation mode during the winter as everyone in Central New York slows down with the increasing cold outside, but there's still plenty happening in the next few weeks provided you dress accordingly.

Gallery Of The Rising Sun

Just in time for the CNY temperatures to take a turn for the colder, a gallery from boston.com of solar images is sure to, er, brighten your day (had to do it). During the last two Summer Seminars that included daytime observing, I was struck by just how little we amateur astronomers seem to dedicate in time and filters to our nearest star (I consider the Bader film covers for my 25×100's an important part of my equipment list). We're fortunate that NASA and major observatories all over the world make solar viewing an important part of their research and that they constantly publish amazing images and movies of solar activity.

Not Enough Minutes In The Day…

newscientist.com reports on the discovery of the "hottest and fastest" planet in town (what did you think they were going to report on?). The new Jupiter-sized planet, appropriately titled WASP-12b, orbits 1/40 of an Astronomical Unit (the distance between the Sun and the Earth) from its host star and whips around this star in about one Earth day. If that was not extreme enough, this new planet has a surface temperature of 2250 oC, as hot as some of the coolest stars in the galaxy.

Jupiter-sized planets originally served as the basis for identifying stars with orbiting planets (because of their gravitational influence on the stars they orbit), now they serve as the celestial Chuck Yeager's of planetary formation, causing scientists to rethink (or just plain throw out) older models of how planets form.

Still Not A Drop To Drink, But You'll Dehydrate More Fashionably Than Ever

Recent observations by the Mars Reconnaissance Orbiter have revealed opal deposits on the surface, which now pushes ahead the window for liquid water on the Martian surface from 3 billion to 2 billion years ago, making that entire window approximately 1.5 billions years long. While I've come to the point of cringing every time I read it, these findings "have implications for the possibility that Mars once supported life." I would be ecstatic to see a photo of a Martian microbe or clam shell on the front of the New York TImes, but the leap from water to organisms is one that EVERY NASA news conference has been very hesitant to even begin to speculate on (did you notice how long it took for NASA presenters to get to the point of even saying "we are now confident that the equipment has provided us evidence for water on the surface" instead of just saying "we found water"?).

The presence of hydrated silica (opal) on the Martian surface marks a new chapter in the geological history of Mars that began with the discoveries of phyllosilicates (from 3.5 billion years ago) and hydrated sulfates (from 3 billion years ago). Opal is formed when liquid water reacts with materials that are formed from either volcanic activity of meteor impact delivery, two types of phenomena that are constant, gradual sources of these new materials (not just from the earliest formation of the planet). That these opal deposits were discovered in reasonably young land formations (geologically speaking, anyway) means that liquid water had to at some point be present in the area. That liquid water has been found to have occurred at this 2 billion year mark only pushes ahead the "end-time" for surface water, which awaits the next discovery from the Mars Reconnaissance Orbiter to bring it still closer to "present day."

RASC Observer's Handbook 2009

You know the New Year is fast approaching when Mike Brady makes mention of the new Observer's Handbook from the Royal Astronomical Society of Canada (RASC). The Observer's Handbook (now in its 101st year of publication) is often regarded as the standard of astronomical tabulation and reference information for observers in North America. If you've not the benefit of two dozen really good web browser bookmarks or a copy of some digital planetarium program (like the free program www.stellarium.org, which is handy to have regardless!) to plan your observing session, the Observer's Handbook is definitely a resource to keep in mind (or in your box of scope accessories).

The RASC even maintains a webpage of updates and corrections to the book (which is worth a regular check if you come to rely on the Handbook for planning your evenings). The soft cover book (at 320 pages) sells for $25.95 + $6.50 S&H (total $32.45). For more information, see the RASC website at www.rasc.ca/handbook/.

And On A Political Note…

While I often avoid publicly taking sides on political issues, something about the last rounds of presidential debates and campaigning really irradiated my outer crust. The John McCain campaign on several occasions (including the presidential candidate himself) complained about Barack Obama's request for a $3 million "overhead projector" in Chicago and how this represented "wasteful extravagance" on the part of the Democratic nominee.

As seems to often be the case in political attacking, the 5-second sound bite leaves out a great deal of information, and even a small amount of investigation reveals a great deal that can speak volumes about a politician's motivations. What the McCain campaign did NOT mention in this petty attack is that the "overhead projector" is actually a planetarium projector to replace the 40 year old Zeiss Mark VI at the Adler Planetarium in Chicago, where over half a million visitors each year see far more of the Night Sky than any large city resident could ever hope to. In a time when educators are VERY concerned about how unprepared for science-related professions America's students are, I think $3 million is an embarrassingly small amount of money to spend in the interest of sparking the public's imagination, especially in a city that hosts the University of Chicago, what MOST Project Director Peter Plumley calls "the greatest science institution in the world."

Perish the thought that any amount of money should go to inspiring and motivating people to pursue their interests in the physical sciences.

Space is the place,
Damian Allis, Ph.D.
sas@somewhereville.com

Links Used Above (Subject To Web Changes)

www.boston.com/bigpicture/2008/10/the_sun.html
www.baader-planetarium.com/sofifolie/sofi_start_e.htm
www.nasa.gov
www.newscientist.com
www.newscientist.com/article/dn14943
en.wikipedia.org/wiki/WASP-12b
en.wikipedia.org/wiki/Astronomical_unit
en.wikipedia.org/wiki/Sun
en.wikipedia.org/wiki/Earth
en.wikipedia.org/wiki/Extrasolar_planet
en.wikipedia.org/wiki/Chuck_Yeager
mars.jpl.nasa.gov/mro/
en.wikipedia.org/wiki/Opal
www.livescience.com/space/0810-28-mars-water-opal.html
www.nytimes.com
en.wikipedia.org/wiki/Mars
en.wikipedia.org/wiki/Phyllosilicates
en.wikipedia.org/wiki/Sulfates
www.rasc.ca/handbook/index.shtml
www.rasc.ca
www.stellarium.org
www.rasc.ca/handbook/updates.shtml
www.johnmccain.com
www.barackobama.com/index.php
www.cityofchicago.org/city/webportal/home.do
www.adlerplanetarium.org/aboutus/index.shtml
www.adlerplanetarium.org
www.uchicago.edu