Henry Rzepa's blog

In an earlier post, I discussed[1] a phenomenon known as the “anomeric effect” exhibited by tetrahedral carbon compounds with four C-O bonds. Each oxygen itself bears two bonds and has two lone pairs, and either of these can align with one of three other C-O bonds to generate an anomeric effect. Here I change the central carbon to a boron to explore what happens, as indeed I promised earlier.

One can identify candidates for such molecules by a constrained search of the CSD or the Cambridge structural database, as shown below.

The four B-O distances for each compound matching the query are now subjected to further analysis, the greatest and least values are identified and the difference between them calculated.

The results are shown in the diagram below. Three outliers are identified for close inspection.

Each of the three candidates is also subjected to a Gaussian calculation (MD15L/Def2-TZVPP)[2] (See DOI: 10.14469/hpc/14092)

1. QIXREW[3]. This molecule is overall neutral and for which Δr_B-O = 0.193Å (MN15L/Def2-TZVPP Δr_{B-O =} 0.175Å). The Wiberg bond indices of longest and shortest B-O bonds are 0.486 and 0.698, Δ = 0.212Å.This is significantly larger than the best example of the C-O series, for which the largest Δr_C-O = 0.074Å and 0.137 for the Wiberg index.
2. XOVZOY[4] is a tri-anion with intercalated Ir³⁺ counterion. Δr_B-O = 0.347Å. A calculation on the isolated tri-anion (with a continuum water field to help emulate the crystal environment) results in the maximum B-O bond length difference of only 0.004Å, which is dramatically different from the crystal structure. This may be an example where the counter-ion is especially important for modelling structure, or it may be simply an anomalous refinement of the crystal structure.
3. KBDCTB, Δr_B-O measured = 0.451Å, Calculated 0.0314Å.
   This is another structure where all may not be what it seems. This again is an anionic structure and geometry optimisation of a single molecule results in a dramatic change in the internal hydrogen bonding of the species. In the crystal structure, the carboxylic acid groups all form intermolecular hydrogen bonds. Optimized as an isolated molecule, the former are no longer possible and a big conformational change occurs to allow all four carboxylic acid groups to instead form intramolecular H-bonds. In this conformation, all four B-O bonds are essentially the same length. So this might well be an example of a large change in anomeric effects due to changes in geometry induced by hydrogen bonding.

   Intermolecular H-bonds	Intramolecular H-bonds

One lesson one always learns when comparing the lengths of bonds observed in crystal structures with those calculated using quantum mechanics is that they sometimes do not match well. These mis-matches can occur for various reasons; changes in hydrogen bonding, or the presence of unmodelled counterions or simply errors in the reported crystal structure. But we might suggest from this brief foray into B-O bonds that the anomeric effects found there may indeed be larger than those of their C-O counterparts.

References

1. H. Rzepa, "Detecting anomeric effects in tetrahedral carbon bearing four oxygen substituents.", 2024. https://doi.org/10.59350/dfkt5-k2b20
2. H. Rzepa, "Detecting anomeric effects in tetrahedral boron bearing four oxygen substituents.", 2024. https://doi.org/10.14469/hpc/14092
3. S.I. Kalläne, T. Braun, B. Braun, and S. Mebs, "Versatile reactivity of a rhodium(i) boryl complex towards ketones and imines", Dalton Transactions, vol. 43, pp. 6786, 2014. https://doi.org/10.1039/c4dt00080c
4. H. Danjo, K. Hirata, S. Yoshigai, I. Azumaya, and K. Yamaguchi, "Back to Back Twin Bowls of <i>D</i>₃-Symmetric Tris(spiroborate)s for Supramolecular Chain Structures", Journal of the American Chemical Society, vol. 131, pp. 1638-1639, 2009. https://doi.org/10.1021/ja8071435

In the mid to late 1990s as the Web developed, it was becoming more obvious that one area it would revolutionise was of scholarly journal publishing. Since the days of the very first scientific journals in the 1650s, the medium had been firmly rooted in paper. Even printed colour only became common (and affordable) from the 1980s. An opportunity to move away from these restrictions was provided by the Web. Early adopters of this medium in chemistry were the CLIC pilot project[1] in 1995 and the Internet Journal of Chemistry (IJC), the latter offering “enhanced chemical publication which permits the publication of materials which cannot be published on paper and end-use customization which permits the readers to read articles prepared for their specific needs“.[2] Publication of the latter started in January 1998, offering “authors the opportunity to enhance their articles by fully incorporating multimedia, large data sets, Java applets, color images and interactive tools.” The journal remained online for seven years, after which it was closed and the articles became inaccessible. By then many major chemistry journals had started evolving along some of the same lines, and it could be argued this journal had served its purpose of alerting both publishers and authors to these new opportunities. Here I describe how an IJC article published in 2001 was brought back to life in more or less the enhanced manner intended.[3]

Entitled “The Mechanism and Design of Asymmetric Co-Arctate Br⁺ (Mobius) Atom Transfers Between Alkenes. A Computational Study“, an abstract of the article is still visible via services such as e.g. Scifinder, but a more complete and open metadata description which can be provided from an assigned DOI (Digital object identifier) is not available, since back in 2001 the adoption of DOIs by journals was still in its infancy. Fortunately, the original source was still available from the authors as a combination of HTML, image files and data, the latter two being hyperlinked into the body of the article. These files are in fact all that is needed to recreate the original IJC article (if not its style), using the mechanism of a data repository[4],[5] rather than that normally designed for a journal. The procedure adopted was as follows:

1. All the data files were uploaded to the repository as a dataset.[6], DOI: 10.14469/hpc/13929.
2. The metadata record generated and registered for these depositions (https://data.datacite.org/application/vnd.datacite.datacite+xml/10.14469/hpc/13929) has Access (the A of FAIR) identifiers in the form of e.g.
   1. <relatedIdentifier relatedIdentifierType="URL" relationType="HasPart">https://data.hpc.imperial.ac.uk/resolve/?doi=13929&file=1</relatedIdentifier>
   2. Descriptive metadata providing further properties if needed, such as file names and media types and file sizes can be obtained via
      • <relatedIdentifier relatedIdentifierType="URL" relationType="HasMetadata">https://data.hpc.imperial.ac.uk/resolve/?ore=13929</relatedIdentifier>
   3. These access identifiers replaced the hyperlinks in the original article HTML
      1. Originally: <a href="supplemental/3-ts-rh3.pdb">-1.5</a>
      2. Becomes: <a href="https://data.hpc.imperial.ac.uk/resolve/?doi=13929&file=54">-1.5</a>
      3. It is worth noting that there are basically two methods of accessing a file. The first relies on its relative path in a hierarchical file system. Hard-coding such a location into a URL means it may not be persistent – the hyperlink is vulnerable to “link rot” when the file system is reorganised and the path to the file changes. The second method relies on a database query, which should be rather more persistent, since the database should always incorporate any reorganisation of the internal systems. A third option (not used here) is to assign a persistent identifier to every file, and to ensure that a properly persistent direct access mechanism is described in metadata for that file.
      4. The root document for the article, given the reserved filename index.html was edited to reflect the changes in the hyperlinks.
3. The article document index.html was now itself uploaded to the repository. In a conventional data repository, such a file invokes no specific actions, but in the repository used for this purpose it does have the reserved meaning of invoking in effect a preview or “LiveView” using the syntax
   • <iframe name="liveview" src="https://data.hpc.imperial.ac.uk/resolve/?doi=13929&file=90"
     width="100%" height="600" id="liveview"></iframe>
4. The article now functions much in the same way it would have done on IJC, albeit in one interesting way. The regular style adopted in journals is to place the ESI or electronic supporting information files into a separate enclave, linked via the article landing page by parochial mechanisms. In this instance the article and its data files are visible on the same page – it is a data repository after all – thus elevating the data to the same status as the article. Such elevation is often referred to as making “Data a first class citizen of the publication processes“.
5. The opportunity now arose to incorporate an interactive tool based on the use of the JSmol molecule viewer.
   • By adding an additional header to the HTML document containing a Javascript invocation of JSmol, selected data could be brought to life by creating a molecular model in a separate window.
   • This is invoked by a variation on the hyperlink shown above in section 3.2 by
     <a href="javascript:show_jmol();javascript:handle_jmol('10.14469/hpc/13933',%20';frame 1;font label 16;zoom 5;moveto 4 90 4 80 65 120;spin 3;set echo bottom left;font echo 20 serif bolditalic;color echo green;echo TS for 3 (C2 symmetry);')">Load 3D Model</a>
   • Additional tools are now provided, from activating a (molecular) vibration, calculating a chirality (if applicable) or others invoked from a pull-down menu.
   • In this example, the data is again accessed directly from a data repository, albeit by a different mechanism from that shown in 3.2 and here based only on the DOI of the data and its media type (in this case chemical/x-mdl-molfile).

It was not the intention here to illustrate how a Journal infrastructure might work – merely to rescue an article published 23 years ago (a long time in the Internet era) from a journal that is no longer disseminating articles. In the process the article has acquired its own DOI (albeit as data and not journal article), something not available from the original journal and some level of interactivity of the type originally envisaged. The (manual) process took something around 2-3 hours to achieve, and would certainly need automating if it were to be used more than once. I take encouragement however that after so many years, it was still possible with relatively little effort to achieve this curation.

References

1. D. James, B.J. Whitaker, C. Hildyard, H.S. Rzepa, O. Casher, J.M. Goodman, D. Riddick, and P. Murray‐Rust, "The case for content integrity in electronic chemistry journals: The CLIC project", New Review of Information Networking, vol. 1, pp. 61-69, 1995. https://doi.org/10.1080/13614579509516846
2. S.M. Bachrach, "The 21st century chemistry journal", Química Nova, vol. 22, pp. 273-276, 1999. https://doi.org/10.1590/s0100-40421999000200020
3. H. Rzepa, "Internet Archeology: an example of a revitalised molecular resource with a new activity now built in.", 2020. https://doi.org/10.59350/9c769-34y25
4. Re3data.Org., "Imperial College Research Computing Service Data Repository", 2016. https://doi.org/10.17616/r3k64n
5. FAIRsharing Team., and , ., "FAIRsharing record for: Imperial College Research Computing Service Data Repository", 2018. https://doi.org/10.25504/fairsharing.letkjt
6. H. Rzepa, "The Mechanism and Design of Asymmetric Co-Arctate Br+ (Mobius) Atom Transfers Between Alkenes. A Computational Study", 2024. https://doi.org/10.14469/hpc/13929

The recent release of the DataCite Data Citation corpus, which has the stated aim of providing “a trusted central aggregate of all data citations to further our understanding of data usage and advance meaningful data metrics” made me want to investigate what the current state of citing data in the area of chemistry might be. Chemistry is known to be a “data rich” science (as most of the physical sciences are) and  here on this very blog I try to cite whenever possible the source(s) of the data that  I often use when discussing a topic. Such citations are not necessarily the same as citing a journal source via e.g. its DOI, although of course one is very likely to find data associated with most articles nowadays, albeit almost entirely via any associated supporting information document. However the latter is often presented in a relatively unstructured (PDF) form, which does not adhere to what are called the “FAIR” guidelines of being findable, accessible, interoperable and reusable. Directly citing data is a way of improving its FAIR-characteristics. So what insights does the Data citation corpus reveal?

1. This overview shows that by far the most common mechanism for citing data is via its Accession Number, used predominantly by Life Sciences (an example of this latter is linked here[1]), with the DOI (digital object identifier) being less common.
   
2. Tunnelling down to citation counts in chemical sciences by publisher, an odd picture emerges with just a handful of citations.
   
3. The more general physical sciences does not fare much better:
4. Lets try a different approach, filtering by repository. Thus here are the statistics for the Cambridge crystallographic data centre, which was citing data in large amounts a few years back, but which appears to have dropped off in the last few years. Given that the entries there continue to go up almost exponentially, we begin to suspect that the data citations there are not being properly recognised as such by the citation corpus.
   
5. Lets try another repository, Zenodo, which again is dropping but where the totals are about 500 a year for the most recent.
6. OK, one more go, the RSC chemistry publisher.
   

I am not sure what to make of this; areas where you would expect very high levels of data citation in chemical sciences do not appear to exist – I think for some reason, the DataCite citation corpus is not yet capturing them.[2] But when things do start operating as perhaps expected, I think we will have a very valuable resource, which should firmly put data (whether FAIR or not) on the map.

References

1. D. Batista, A. Gonzalez-Beltran, S. Sansone, and P. Rocca-Serra, "Machine actionable metadata models", Scientific Data, vol. 9, 2022. https://doi.org/10.1038/s41597-022-01707-6
2. R. Page, "Problems with the DataCite Data Citation Corpus", 2024. https://doi.org/10.59350/t80g1-xys37

In the late 1980s, as I recollected here[1] the equipment needed for real time molecular visualisation as it became known as was still expensive, requiring custom systems such as Evans and Sutherland PS390 workstations. One major breakthrough in making such techniques generally available on less specialised equipment was achieved by Roger Sayle[2], then working at Imperial College around 1990 and using a Silicon Graphics workstation. He greatly optimised up the rendering algorithms by creating a program called RasMol (after his initials), which meant such visualisations could very rapidly also be achieved even on a personal computer. Moving from vector display technology (the PS390) to Raster/bitmap graphics had allowed spacefilling representations of molecules containing 100s if not 1000s of atoms – and in turn enabled the new World-Wide Web to exploit the technique.[3]

Whilst Rasmol is very much still around, it also provided an inspiration for successor programs such as Jmol (based on Java) and JSMol (based on the Javascript language built into all modern web browsers). There are now many articles in the literature describing this program. In 2008 the very first post on this blog described how run it in a WordPress instance[4].

Now a new milestone in molecular visualisation has been reached – the ability to display 3 million atoms! Bob Hanson has just released Jmol/JSmol 16.1.51 which supports the BinaryCIF file format. An example of the power of both program and this new format is illustrated with the protein 8glv[5] which contains 3 million atoms (the bcif file itself is only 47.4 Mb).

The Jmol/JSmol script to load it is:

t = now();    
     set autobond false;
     load =8glv.bcif filter "*.C";
     spacefill on;
     color chain;
     print now(t);

and the actual rendering takes just 10-20 seconds. You can see from the screenshots below^‡ that when it is zoomed in, it really does show individual atoms! Who knows what the practical atom limit is, but it is almost certainly more than three million! And it may even be possible on a mobile phone!

^‡OK, you are asking why I have not loaded 8glv into this page? Well, I need to update JSmol on this site first, and have encountered an issue that needs fixing.

References

1. H. Rzepa, "Computers 1967-2011: a personal perspective. Part 2. 1985-1989.", 2011. https://doi.org/10.59350/g4j62-4xk50
2. R. Sayle, "RASMOL: biomolecular graphics for all", Trends in Biochemical Sciences, vol. 20, pp. 374-376, 1995. https://doi.org/10.1016/s0968-0004(00)89080-5
3. H.S. Rzepa, B.J. Whitaker, and M.J. Winter, "Chemical applications of the World-Wide-Web system", Journal of the Chemical Society, Chemical Communications, pp. 1907, 1994. https://doi.org/10.1039/c39940001907
4. H. Rzepa, "Jmol and WordPress: Loading 3D molecular models, molecular isosurfaces and molecular vibrations into a blog", 2008. https://doi.org/10.59350/pq7ds-gqr71
5. T. Walton, and A. Brown, "96-nm repeat unit of doublet microtubules from Chlamydomonas reinhardtii flagella", 2023. https://doi.org/10.2210/pdb8glv/pdb

On 24th January 1984, the Macintosh computer was released, as all the media are informing us. Apparently, some are still working. I thought I would give my own personal recollections of that period.

In fact, the Mac reached UK stores via a dealership only in 1985. What brought it to the attention of our university chemistry department was that also in 1985 the Chemdraw program was released and visitors to e.g. ACS meetings that year (probably the spring meeting) brought news of it back. A third piece of the puzzle, the Laserwriter also appeared that year. What difference would all this make? Well, take a look at the diagram in this 1983 article[1]. I drew that with stencils and transfer lettering, and the diagrams in this article took me ages! The article was submitted to what was called a “camera ready” journal, as part of the process of accelerating its publication, so it had to be as perfect as I could make it. I had to start from the beginning several times, since sometimes even Typex could not fix the errors or rescue the diagram from being a bit to big to fit onto the Journal provided template.

After drafting these diagrams, I vowed never again! Fortunately, the Mac, Chemdraw and the Laserwriter appeared some 18 months later! I remember going around the (mostly organic) chemists in the department, asking if they would like to join in a bulk purchase and we ended up with 10 Macs. By 1985, the model had moved on to the Mac 512K which were the ones actually purchased and photos of the front and rear of one are shown below (I still have it, hoping a collector might make me an offer one day).

The first year of use revealed an infamous quirk. The port on the rear of the Mac 512K did not support attachment of any hard drives (although in 1985 these were ferociously expensive for a 10 MB drive!) and so most of the time one spent not using eg Chemdraw but pushing floppy disks in and out of the machine. A year later, the Mac Plus 1Mb version was introduced (third photo) and this had a SCSI port. I attached such a 10 Mbyte drive to this port and the bliss at not having to rotate floppy disks was immense.

Back to the 512K model. After they were delivered, I gathered all 9 other users and introduced them all to the mouse. In the first 15 minutes, there were rumblings that they would never get used to such a strange object, but at roughly the 45 minute mark, they were all converts. The program demonstrated was of course Chemdraw. Microsoft Word was not yet available but another simple word processor was (WriteNow) and everyone practised constructing diagrams such as the above. What joy! And no Typex, or starting the diagram from scratch – merely a simple 10 second edit.

By 1987 as I recollect, there were many 1MB models now installed and we set about networking them all together and connecting them to the Laserwriter. We even managed to use the Mac to connect to STN international to search Chemical Abstracts[2] and the modern era was well under way.

So this is my tribute to the Mac on its 40th birthday. I still use them to this day.

References

1. A.M. Lobo, S. Prabhakar, H.S. Rzepa, A.C. Skapski, M. Tavers, and D.A. Widdowson, "C-substitution reactions of c,n-diaryl nitrones", Tetrahedron, vol. 39, pp. 3833-3841, 1983. https://doi.org/10.1016/s0040-4020(01)88625-7
2. H. Rzepa, "A trip down memory lane: An online departmental connection map from 1989.", 2023. https://doi.org/10.59350/85xp6-2sy65

Zosurabalbin[1],[2], is receiving a great deal of attention as a new class of antibiotic which can target infections for which current treatment options are inadequate. It is a cyclic peptide and seeing this triggered memory of an earlier such species reported way back in 1995[3],[4]. This octa-peptide (YIJDIE, DOI: 10.5517/cc58gxs) was presumed to function in a novel manner, having linear water channels wide enough to form a molecular nanoscale pipe for a stream of water molecules to flow along. When inserted into the bacterial cell membrane via its lipophilic sidechains, it drained the bacterium of its cell water within seconds, thus killing it. A 3D model shows the effect very clearly.

Zosurabalpin does not function in this manner. Its structure was devised by optimising the various substituents until optimal activity was obtained (see this patent WO202319441).

The ligand (VB6) is seen below. A program such as Chimera can tease out many more details.

Zosurabalpin embedded in the protein pdb8frn can be viewed below and the coordinates can be obtained via DOI: 10.2210/pdb8frn/pdb

The original 1995 report[3] about the cyclic octapeptide appears was never developed into a clinically useful antibiotic, but I wonder where this approach led to.

References

1. C. Zampaloni, P. Mattei, K. Bleicher, L. Winther, C. Thäte, C. Bucher, J. Adam, A. Alanine, K.E. Amrein, V. Baidin, C. Bieniossek, C. Bissantz, F. Boess, C. Cantrill, T. Clairfeuille, F. Dey, P. Di Giorgio, P. du Castel, D. Dylus, P. Dzygiel, A. Felici, F. García-Alcalde, A. Haldimann, M. Leipner, S. Leyn, S. Louvel, P. Misson, A. Osterman, K. Pahil, S. Rigo, A. Schäublin, S. Scharf, P. Schmitz, T. Stoll, A. Trauner, S. Zoffmann, D. Kahne, J.A.T. Young, M.A. Lobritz, and K.A. Bradley, "A novel antibiotic class targeting the lipopolysaccharide transporter", Nature, vol. 625, pp. 566-571, 2024. https://doi.org/10.1038/s41586-023-06873-0
2. S. Hawser, N. Kothari, T. Valmont, S. Louvel, and C. Zampaloni, "2131. Activity of the Novel Antibiotic Zosurabalpin (RG6006) against Clinical <i>Acinetobacter</i> Isolates from China", Open Forum Infectious Diseases, vol. 10, 2023. https://doi.org/10.1093/ofid/ofad500.1754
3. M.R. Ghadiri, K. Kobayashi, J.R. Granja, R.K. Chadha, and D.E. McRee, "The Structural and Thermodynamic Basis for the Formation of Self‐Assembled Peptide Nanotubes", Angewandte Chemie International Edition in English, vol. 34, pp. 93-95, 1995. https://doi.org/10.1002/anie.199500931
4. S. Fernandez-Lopez, H. Kim, E.C. Choi, M. Delgado, J.R. Granja, A. Khasanov, K. Kraehenbuehl, G. Long, D.A. Weinberger, K.M. Wilcoxen, and M.R. Ghadiri, "Antibacterial agents based on the cyclic d,l-α-peptide architecture", Nature, vol. 412, pp. 452-455, 2001. https://doi.org/10.1038/35086601