Mspin, RDC’s and efficient use of freely rotating groups

In the last ten years, Residual Dipolar Couplings (RDC) have come to occupy a very important place in the structure determination of proteins, nucleic acids and carbohydrates in liquid state. Although RDCs were originally discovered and theoretically explained for small molecules in liquid crystal solvents by A. Saupe in 1968 (Angew. Chem. Int. Ed. Engl. 1968, 7, 97) the spectra were too complex for a practical use in structure determination. The discovering of weak orienting media in water led to an explosion in the application of RDCs for biomolecule structure determination. However, those aligning media used for biomolecules were not applicable to most of the small molecules. Fortunately, recent research results considerably extended the applications of RDCs to small molecules as new alignment media for organic solvents, either liquid crystal type as poly-?-benzyl-L-glutamate (PBLG), or mechanically stretched cross-linked polymer gels such as poly(methyl methacrylate) gel (PMMA) or polydimethylsiloxane (PDMS) are available. If you are interested in RDCs you should certainly check the very didactic introduction in the theory by Kramer et al. Applications and practical considerations are nicely reviewed in the recent reviews by Cristina Thiele ( See this and this) and Burkhard Luy ( see this).

The use of RDCs in small molecule structural determination is typically based on the determination of the alignment tensor, a 3x3 matrix, which contains the information about the probability of the molecule pointing in a particular direction of the space. This matrix can be determined by least squares fitting to the experimental RDCs.
However, there exists a further potential problem on the application of RDC to the structure determination of small molecules: the lack of enough independent RDCs, i.e, those coming from non parallel vectors, since in most cases only 1DCH RDCs are available from F1 ( see this) or F2 coupled (see this ) HSQC type experiments, thus making the fitting problem underdetermined. Armando Navarro et al. have recently proposed an elegant approach to get the most out of the experimental data by incorporating into the calculations two of the most common freely rotating groups, namely the methyl and phenyl groups (using 2-fold and 3-fold jump models).

The authors have automated this averaging of RDCs from freely rotating groups in version 1.03 of our program Mspin which we hope will facilitate the use of RDC among a broader community of users interested in solving structural questions of small molecules

New Mestrelab Blog

I’m happy to announce our new blog on Mestrelab. As Santi wrote, the purpose of this blog is “to report on company progress and ideas, to tell stories about our trips and conferences, and to highlight aspects of our products which we may think our users may be interested in reading, or hearing, about”
A lot of people seemed to be very interested in what we're doing in Mestrelab so we thought that it would be helpful to create this blog so as to keep you all up to date on what’s going on with our commercial initiatives, trips (including photo sets from those trips) etc.
So if you feel curious about Mestrelab activities, please visit our new blog. We look forward to hearing from you.

Mestrelab's blog: http://blog.mestrec.com

NMR Spectroscopy Explained

When I initiated the development of MestReC back in 1995 (15 years ago!), my knowledge of NMR was fairly elementary and limited to basic theoretical rudiments (quantum mechanics description of NMR phenomenon, vector model, etc) and some experience in the practical interpretation of NMR spectra gained primarily whilst working as an organic chemist at Leicester University.

That said, during that first phase of development, I wish I had enjoyed the opportunity to have access to the book ‘NMR Spectroscopy Explained: Simplified Theory, Applications and Examples for Organic Chemistry and Structural Biology' by Neil Jacobson, I’m sure that my productivity would have been boosted very significantly by it. For example, there is an unmissable section devoted to practical NMR aspects and, in particular, NMR data acquisition and processing. It’s clear from this section that the book was written from the perspective of a spectroscopist who works with NMR on a day-to-day basis (Neil Jacobsen is the NMR Facility Manager at the University of Arizona). Concepts such as oversampling and digital filtering are presented in more detail than that found in standard introductory texts. I bought this book about 6 months ago and I have to say that it is a shame that it wasn’t available much earlier when I started my work on NMR.

Nothing is ever perfect and if I had to point out something missing in the book it would be a chapter devoted to DOSY, which I think would make a nice addition.

Overall, I believe that this is a great book which I warmly recommend to all of you who wish to deepen your understanding of NMR both from a practical and theoretical standpoint. Enjoy, and let me have your thoughts!

Mnova reviewed by Tim Claridge at JCIM

High-Resolution NMR Techniques in Organic Chemistry is one of the most popular books on NMR which is now used at many universities as a foundation for graduate-level courses on NMR techniques. It has been written by Tim Claridge who is the Director of NMR Spectroscopy at the Organic Chemistry Department at Oxford University and has now written a very nice review on Mnova in the Journal of Chemistry Information and Modeling (JCIM). I'll just quote one of his conclusions because I'd rather let you read the full article:

Overall I was very impressed with the package, finding it not only very comfortable and intuitive to use so well suited to non-NMR specialist, but also well endowed with more advanced processing features for more experienced users

(Click here for the full article)

I would like to take this opportunity to thank all of you for your support, advice and contributions to our design and development, and also congratulate my team; it seems we are doing well at developing easy to use but powerful NMR software. But don’t worry, we are not going to get complacent because of reviews like this, on the contrary, they are just a spur to work harder and develop the software further

Article bookmark. Tim Claridge University of Oxford J. Chem. Inf. Model., Article ASAP DOI: 10.1021/ci900090d Publication Date (Web): March 30, 2009 http://pubs.acs.org/doi/abs/10.1021/ci900090d Copyright © 2009 American Chemical Society

Pre-ENC User Meeting Video

As you may know, we are going to hold an user meeting prior to the 50th ENC Conference.
There, Mestrelab's team and some guests are going to present some new Mnova features, algorythms and new products.

You can check the meeting program and get registered here.
Whether you are planning to attend or not I also encourage you to watch this 5 minutes video.

Double-click to switch to full screen

Pre-ENC User Video from Dani Fraga on Vimeo.

NMR and the Chemist’s Illusion

Stan has just posted a nice entry in which he uses the aromatic region of Strychnine to discourse about the different effects in the NMR spectrum (in terms of resolution and multiplicity) produced when the magnetic field frequency is changed. In particular, I like his description of the ‘Chemist’s Illusion’ and as a chemist, I would like to illustrate, just with a picture, what this illusion is all about.

In the picture below, I have synthesized the ABCD spin system corresponding to the aromatic region of Strychnine at different fields (we don’t own a 1500 MHz spectrometer and we don’t expect to get one for Mestrelab in the short- or mid-term :-) ). It can be appreciated that as we move to higher fields, the multiplets appear to be more separated (this is an illusion: their chemical shifts, in ppm, are exactly the same!) and get more resolved and more first-order like.

Below I’m showing an expansion of the right most multiplets:


Another interesting and well known example is represented by an AA’BB’ spin system (for example, o-diclhrobenzene) . Again, as we go to higher fields, the apparent multiplets separation looks larger, although the multiplet fine structure remains virtually unchanged. In other words, in these systems, second order effects will always exist regardless of the magnetic field. When the magnetic field is increased, it will be possible to get a larger chemical shift difference between the AA’ and the BB’ groups, but not between A and A’ or B and B’ (it’s always zero), so that the highest simplification one can achieve by increasing the magnetic field is to move from an AA’BB’ group to an AA’XX’ group which is a second order spin system too.

Peak Shapes in NMR Spectroscopy

Routine analysis of NMR data involves peak picking and integration to get chemical shifts (and couplings) and quantitative information (e.g. number of protons). When the peaks are not well resolved, none of these parameters can be accurately estimated and nonlinear least squares fit (curve fitting or deconvolution) is often performed to extract the desired information. However, deconvolution presents, at least two important difficulties:

Problem #1

In general, line fitting is applied to some limited number of lines in a spectrum as a deconvolution of the full spectrum is very difficult to say the least. This implies a manual intervention of the User (choice of multiplet, specification of the number of lines and of their starting parameters).

Problem #2

Curve fitting requires the definition of an analytical model for the line shape and in particular, NMR lineshaphes have typically been assumed to be either Lorentzian, Gaussian, or a combination of both (e.g. Voight Profile). The problem is that Lorentzian deconvolutions are numerically ill defined because all complete sets of Lorentzian-shaped functions are approximately linearly dependent (in other words, a Lorentzian peak can be approximated very well by several Lorentzian lines). This problem is specially important in 1H-NMR spectra where peaks are really complicated envelopes of many unresolved transitions (for example, in a generic 10 spin system there are 5120 distinct main transitions, but one typically resolves less than 100 peaks).

These problems have been the motivation of the development of a brand new peak analysis algorithm, the so-called GSD (Global Spectral Deconvolution) which has been recently presented by Stan Sykora in a talk he gave at MMCE 2009 conference. In fact, GSD is now fully operative within MestReNova .

If you are interested in GSD and planning to visit ENC, we will be pleased to show you every detail at the user meeting we will keep on Sunday 29th March and at our exhibitor and hospitality suite (you do not need to be a MestReNova User to participate).

DOSY-shift reagents

A well-known procedure to separate resonances that would otherwise overlap in crowded NMR spectra is by adding to the sample some paramagnetic substance, the so-called shift-reagent. The most commonly used shift reagents are complexes of paramagnetic lanthanide ions such as europium(III) for down field shifts and praseodymium(III) for upfield shifts.

A similar approach has been recently reported to resolve mixture components via DOSY-NMR. It’s not very uncommon that in some mixture analyses, 2 or more compounds have diffusion coefficients so similar that they cannot be resolved by any mathematical procedure. For example, the figure below shows a synthetic DOSY spectrum (based on Figure 2 of the original article) of a mixture of two peptides, Trp-Gly and Leu-Met having D values nearly identical

M. E. Zielinski and K. F. Morris proposed in their article to add perdeuterated surfactant micelles to the mixture. Analogous to the chemical offsets induced by shift reagents, the molecules in the mixture under analysis interact differentially with the micelles and thus have different Diffusion values.

Using perdeuterated surfactant micelles to resolve mixture components in diffusion-ordered NMR spectroscopy
Matthew E. Zielinski, Kevin F. Morris, Magnetic Resonance in Chemistry
Volume 47 Issue 1, Pages 53 - 56

Microreview on NMR structural elucidation

A nice short review presenting practical strategies for the elucidation of small organic molecules with NMR spectroscopy has been published a few months ago. I highly recommend it as a reference for organic chemists engaged in structural elucidation tasks.

Eugene E. Kwan, Shaw G. Huang, Structural Elucidation with NMR Spectroscopy: Practical Strategies for Organic Chemists European Journal of Organic Chemistry, 2008 (16), 2671-2688

DOI: 10.1002/ejoc.200700966

Better NMR Processing and Analysis with Mnova 5.3.0

I’m pleased to announce the release of the latest version of Mnova (version 5.3.0), our software for the efficient processing, analysis and prediction of NMR spectra.
With the unveiling of version 5.3.0 come a multitude of enhancements over previous releases . Here I’d just like to highlight some key new features which I’m very proud of as I think they represent a substantial enhancement in the software’s capabilities and, in some cases, new breakthroughs in the world of NMR software:

• Bayesian DOSY Processing
• Whitening algorithm for 2D automatic Phase Correction
• Prediction of X-Nuclides spectra
• Spin Simulation module with support for scalar, dipolar and quadrupolar interactions and its unique classification of transitions feature
• Covariance NMR: Direct, Indirect and Unsymmetrical by means of the Advanced Arithmetic Module
• Multipoint (manual) Baseline Correction

We have also greatly improved some algorithms such as peak picking, automatic noise estimation, resolution booster, integration, etc.
It’s also worth mentioning that most of the new dialog boxes in the program are modeless. For example, now while phase correcting a spectrum, you can zoom in to a particular spectral region without having to quit the phase correction dialog.
There are many other new features in this new version, and many more to come shortly in forthcoming updates. I will be featuring some of them in future posts.
I would like to take this opportunity to congratulate our development team on the fantastic work they have done. Big thanks, guys!

Note. This version will be available for download from our web site Friday 19th