Posts Tagged ‘MDS’

Energetics of cations moving within G-Quadruplex DNA

February 8, 2012 14 comments
Parisa Akhshi, Nicholas J. Mosey, Gang Wu*
Angew Chem Int Ed Engl. 2012 Jan 13. doi: 10.1002/anie.201107700.
PMID: 22241618
A synopsis by Mariana Martín-Hidalgo

Gang Wu and coworkers are presenting in this short communication a molecular dynamic simulation to elucidate the free-energy landscape for the movement of three monovalent cations (Na+, K+, NH4+)through the central channel of a tetramolecular oligo G-quadruplex (OGQ).  The importance of this work strikes in the potential use of OGQs as synthetic ion channels, an application that has been considered by a number of research groups in last decade.

To perform this study they divided the ion movement in two regions: inside the OGQ and at the entrance/exit region.  They found that for the inner OGQ region, Na+ showed a lower energy barrier (4-5 kcal/mol) when compared to K+ and NH4+ (13-15 kcal/mol).  They made reference to experimental data to backup these computational results, plus they argue that the ionic radii differences between them are responsible for the observed energy barriers.  K+ and NH4+ have similar ionic radii (1.51 and 1.66 Å for octahedral coordinate ions respectively) while Na+ (1.18 Å) being a little bit smaller can diffuse through the tetrads easily.

They also highlighted the possibility of having what they refer to as “leaks” through the tetrad (sideway movement of ions) instead of the proposed continuous ion movement through the central channel.  They basically found that the energy barrier for that ion movement is too high (50-60 kcal/mol) to make it possible, discarding this possibility. I have to bring an issue related to their expression in this paragraph (second page, first paragraph), because they mentioned and I cite: “ there has never been experimental proof that ions would not “leak” out from the side wall of the G-quadruplex channel”.  I know the authors are emphasizing in the study of ion movement for OGQ’s but we know that there are OGQs and supramolecular GQs (SGQs) self-assembled from a variety of guanine derivatives. So, in my view they should’ve specified that lateral ion movement haven’t been shown for OGQs (perhaps in a note), but it had for SGQs. Specifically, in 2006 the Davis group reported (JACS 128 (47), 15269) the first evidence of “sideway” displacement for cations in a four-tetrad (4T) SGQ (i.e. a hexadecamer formed from the dimerization of two octamers). The mechanism of exchange of course would be different in a 4T-SGQ like Davis’ when compared to Wu’s 4T-OGQ and we can discuss those on Fridays presentation.

In the second region, the entrance/exit sides, the energy barrier encountered for K+ and NH4+ was 20 kcal/mol, while for Na+ was 14 kcal/mol, both values correlate well with the experimental data reported in the literature. Another important point of discussion the hydration states of these cations.  The inner cations are fully dehydrated while the ones located at the entrance/exit positions might be hydrated because of the transition to/from the bulk media.

From my point of view the most important part of this report is their comparison with a potassium ion channel.  All the gathered computational data reveals that the use of this or related sequences as K+ channels need to overcome significant energy barriers, even for the smaller Na+, if they are to be used as synthetic ion channels.

Although my technical knowledge of how to perform MDS is minimal, they contribute a very important part for the development of a molecular research project.  I think it will be great to have some fundamental MDS studies for some of our derivatives in relation to the ion movement not only in organic media, but also in aqueous environments.  As we have discovered in recent years, not all SGQs behave the same even if they have the same central guanine core in common.  Cations play a very important role in controlling these assemblies and I believe there is a need to put more effort in this regard, in particular with our system.  Any volunteers?

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