Category Archives: Paper
Collaborations in Inorganic Chemistry
I began my path in computational chemistry while I still was an undergraduate student, working on my thesis under professor Cea at unam, synthesizing main group complexes with sulfur containing ligands. Quite a mouthful, I know. Therefore my first calculations dealt with obtaining Bond indexed for bidentate ligands bonded to tin, antimony and even arsenic; yes! I worked with arsenic once! Happily, I keep a tight bond (pun intended) with inorganic chemists and the recent two papers published with the group of Prof. Mónica Moya are proof of that.
In the first paper, cyclic metallaborates were formed with Ga and Al but when a cycle of a given size formed with one it didn’t with the other (fig 1), so I calculated the relative energies of both analogues while compensating for the change in the number of electrons with the following equation:
Fig 1
Under the same conditions 6-membered rings were formed with Ga but not with Al and 8-membered rings were obtained for Al but not for Ga. Differences in their covalent radii alone couldn’t account for this fact.
ΔE = E(MnBxOy) – nEM + nEM’ – E(M’nBxOy) Eq 1
A seamless substitution would imply ΔE = 0 when changing from M to M’
Hipothetical compounds optimized at the B3LYP/6-31G(d,p) level of theory
The calculated ΔE were: ΔE(3/3′) = -81.38 kcal/mol; ΔE(4/4′) = 40.61 kcal/mol; ΔE(5/5′) = 70.98 kcal/mol
In all, the increased stability and higher covalent character of the Ga-O-Ga unit compared to that of the Al analogue favors the formation of different sized rings.
Additionally, a free energy change analysis was performed to assess the relative stability between compounds. Changes in free energy can be obtained easily from the thermochemistry section in the FREQ calculation from Gaussian.
This paper is published in Inorganic Chemistry under the following citation: Erandi Bernabé-Pablo, Vojtech Jancik, Diego Martínez-Otero, Joaquín Barroso-Flores, and Mónica Moya-Cabrera* “Molecular Group 13 Metallaborates Derived from M−O−M Cleavage Promoted by BH3” Inorg. Chem. 2017, 56, 7890−7899
The second paper deals with heavier atoms and the bonds the formed around Yttrium complexes with triazoles, for which we calculated a more detailed distribution of the electronic density and concluded that the coordination of Cp to Y involves a high component of ionic character.
This paper is published in Ana Cristina García-Álvarez, Erandi Bernabé-Pablo, Joaquín Barroso-Flores, Vojtech Jancik, Diego Martínez-Otero, T. Jesús Morales-Juárez, Mónica Moya-Cabrera* “Multinuclear rare-earth metal complexes supported by chalcogen-based 1,2,3-triazole” Polyhedron 135 (2017) 10-16
We keep working on other projects and I hope we keep on doing so for the foreseeable future because those main group metals have been in my blood all this century. Thanks and a big shoutout to Dr. Monica Moya for keeping me in her highly productive and competitive team of researchers; here is to many more years of joint work.
Stability of Unnatural DNA – @PCCP #CompChem
As is the case of proteins, the functioning of DNA is highly dependent on its 3D structure and not just only on its sequence but the difference is that protein tertiary structure has an enormous variety whereas DNA is (almost) always a double helix with little variations. The canonical base pairs AT, CG stabilize the famous double helix but the same cannot be guaranteed when non-canonical -unnatural- base pairs (UBPs) are introduced.
Figure 1
When I first took a look at Romesberg’s UBPS, d5SICS and dNaM (throughout the study referred to as X and Y see Fig.1) it was evident that they could not form hydrogen bonds, in the end they’re substituted naphtalenes with no discernible ways of creating a synton like their natural counterparts. That’s when I called Dr. Rodrigo Galindo at Utah University who is one of the developers of the AMBER code and who is very knowledgeable on matters of DNA structure and dynamics; he immediately got on board and soon enough we were launching molecular dynamics simulations and quantum mechanical calculations. That was more than two years ago.
Our latest paper in Phys.Chem.Chem.Phys. deals with the dynamical and structural stability of a DNA strand in which Romesberg’s UBPs are introduced sequentially one pair at a time into Dickerson’s dodecamer (a palindromic sequence) from the Protein Data Bank. Therein d5SICS-dNaM pair were inserted right in the middle forming a trisdecamer; as expected, +10 microseconds molecular dynamics simulations exhibited the same stability as the control dodecamer (Fig.2 left). We didn’t need to go far enough into the substitutions to get the double helix to go awry within a couple of microseconds: Three non-consecutive inclusions of UBPs were enough to get a less regular structure (Fig. 2 right); with five, a globular structure was obtained for which is not possible to get a proper average of the most populated structures.
X and Y don’t form hydrogen bonds so the pairing is pretty much forced by the scaffold of the rest of the DNA’s double helix. There are some controversies as to how X and Y fit together, whether they overlap or just wedge between each other and according to our results, the pairing suggests that a C1-C1′ distance of 11 Å is most stable consistent with the wedging conformation. Still much work is needed to understand the pairing between X and Y and even more so to get a pair of useful UBPs. More papers on this topic in the near future.
Unnatural DNA and Synthetic Biology
Ever since I read the highly praised article by Floyd Romesberg in Nature back in 2013 I got really interested in synthetic biology. In said article, an unnatural base pair (UBP) was not only inserted into a DNA double strand in vivo but the organism was even able to reproduce the UBPs present in subsequent generations.
Romesberg’s Nucleosides. No Hydrogen bonding is formed between them!
Inserting new unnatural base pairs in DNA works a lot like editing a computer’s code. Inserting a couple UBPs in vitro is like inserting a comment; it wont make a difference but its still there. If the DNA sequence containing the UBPs can be amplified by molecular biology techniques such as PCR it means that a polymerase enzyme is able to recognize it and place it in site, this is equivalent to inserting a ‘hello world’ section into a working code; it will compile but it’s pretty much useless. Inserting these UBPs in vivo means that the organism is able to thrive despite the large deformation in a short section of its genetic code, but having it replicated by the chemical machinery of the nucleus is an amazing feat that only a few molecules could allow.
The ultimate goal of synthetic biology would be to find a UBP which codes effectively and purposefully during translation of DNA.This last feat would be equivalent to inserting a working subroutine in a program with a specific purpose. But not only could the use of UBPs serve for the purposes of expanding the genetic code from a quaternary (base four) to a senary (base six) system: the field of DNA origami could also benefit from having an expansion in the chemical and structural possibilities of the famous double helix; marking and editing a sequence would also become easier by having distinctive sections with nucleotides other than A, T, C and G.
It is precisely in the concept of double helix that our research takes place since the available biochemical machinery for translation and replication can only work on a double helix, else, the repair mechanisms get activated or the DNA will just stop serving its purpose (i.e. the code wont compile).
My good friend, Dr. Rodrigo Galindo and I have worked on the simulation of Romesberg’s UBPs in order to understand the underlying structural, dynamical and electronic causes that made them so successful and to possibly design more efficient UBPs based on a set of general principles. A first paper has been accepted for publication in Phys.Chem.Chem.Phys. and we’re very excited for it; more on that in a future post.
New paper in Tetrahedron #CompChem “Why U don’t React?”
Literature in synthetic chemistry is full of reactions that do occur but very little or no attention is payed to those that do not proceed. The question here is what can we learn from reactions that are not taking place even when our chemical intuition tells us they’re feasible? Is there valuable knowledge that can be acquired by studying the ‘anti-driving force’ that inhibits a reaction? This is the focus of a new manuscript recently published by our research group in Tetrahedron (DOI: 10.1016/j.tet.2016.05.058) which was the basis of Guillermo Caballero’s BSc thesis.
It is well known in organic chemistry that if a molecular structure has the possibility to be aromatic it can somehow undergo an aromatization process to achieve this more stable state. During some experimental efforts Guillermo Caballero found two compounds that could be easily regarded as non-aromatic tautomers of a substituted pyridine but which were not transformed into the aromatic compound by any means explored; whether by treatment with strong bases, or through thermal or photochemical reaction conditions.
These results led us to investigate the causes that inhibits these aromatization reactions to occur and here is where computational chemistry took over. As a first approach we proposed two plausible reaction mechanisms for the aromatization process and evaluated them with DFT transition state calculations at the M05-2x/6-31+G(d,p)//B3LYP/6-31+G(d,p) levels of theory. The results showed that despite the aromatic tautomers are indeed more stable than their corresponding non-aromatic ones, a high activation free energy is needed to reach the transition states. Thus, the barrier heights are the first reason why aromatization is being inhibited; there just isn’t enough thermal energy in the environment for the transformation to occur.
But this is only the proximal cause, we went then to search for the distal causes (i.e. the reasons behind the high energy of the barriers). The second part of the work was then the calculation of the delocalization energies and frontier molecular orbitals for the non-aromatic tautomers at the HF/cc-pVQZ level of theory to get insights for the large barrier heights. The energies showed a strong electron delocalization of the nitrogen’s lone pair to the oxygen atom in the carbonyl group. Such delocalization promoted the formation of an electron corridor formed with frontier and close-to-frontier molecular orbitals, resembling an extended push-pull effect. The hydrogen atoms that could promote the aromatization process are shown to be chemically inaccessible.
Further calculations for a series of analogous compounds showed that the dimethyl amino moiety plays a crucial role avoiding the aromatization process to occur. When this group was changed for a nitro group, theoretical calculations yielded a decrease in the barrier high, enough for the reaction to proceed. Electronically, the bonding electron corridor is interrupted due to a pull-pull effect that was assessed through the delocalization energies.
The identity of the compounds under study was assessed through 1H, 13C-NMR and 2D NMR experiments HMBC, HMQC so we had to dive head long into experimental techniques to back our calculations.
New Paper in JIPH – As(V)@calix[n]arenes
As part of an ongoing collaboration with the University of Arizona (UA) and the Center for Advanced Research and Studies (CINVESTAV – Saltillo), we are looking into the use of calix[n]arenes for bio-remediation agents capable to extract Arsenic (V) and (III) species from water. Water contamination by arsenic is a pressing issue in northern Mexico and the southern US, therefore any efforts aiming to their elimination has strong social and health repercussions.
As in previous studies, all calixarenes were optimized along with their corresponding guests within the cavity, namely H3AsO4, H2AsO4– and HAsO42- at the DFT level with the so-called Minnesota functionals by Truhlar and Cao, M06-2X/6-31G(d,p) level of theory. Interaction energies were calculated through the NBODel procedure. Calixarenes with R = SO3H and PO3H are the most promising leads. This study is now publishes in the Journal of Inclusion Phenomena and Macrocyclic Chemistry (DOI 10.1007/s10847-016-0617-0) as an online first article.
This article is also the first to be published by our undergraduate (and almost grad student in a month) Gustavo Mondragón who took this project on a side to his own research on photosynthesis.
Now my colleagues in Arizona and Saltillo, Prof. Reyes Sierra and Dr. Eddie López, respectively, will work on the experimental side of the project. Further calculations are being undertaken to extend this study to As(III) and to the use of other potential extracting materials such as metallic nanoparticles to which calixarenes could be covalently linked.
Fluorescent Chemosensors for Chloride in Water – Sensors and Actuators B: Chemical
A new publication is now available in which we calculated the binding properties of a fluorescent water-soluble chemosensor for halides which is specially sensitive for chloride. Once again, we were working in collaboration with an experimental group who is currently involved in developing all kinds of sustainable chemosensors.
The electronic structure of the chromophore was calculated at the M06-2X/6-311++G(d,p) level of theory under the SMD solvation model (water) at various pH levels which was achieved simply by changing the protonation and charges upon the ligand. Wiberg bond indexes from the Natural Population Analysis showed strong interactions between the chloride ion and the chromophore. Also, Fukui indexes were calculated in order to find the most probable binding sites. A very interesting feature of this compound is its ability to form a cavity without being a macrocycle! I deem it a cavity because of the intramolecular interactions which prevent the entrance of solvent molecules but that can be reversibly disrupted for the inclusion of an anion. In the figure below you can observe the remarkable quenching effect chloride has on the anion.
A quick look to the Frontier Molecular Orbitals (FMO’s) show that the chloride anion acts as an electron donor to the sensor.
Frontier Molecular Orbitals
If you are interested in more details please check: Bazany-Rodríguez, I. J., Martínez-Otero, D., Barroso-Flores, J., Yatsimirsky, A. K., & Dorazco-González, A. (2015). Sensitive water-soluble fluorescent chemosensor for chloride based on a bisquinolinium pyridine-dicarboxamide compound. Sensors and Actuators B: Chemical, 221, 1348–1355. http://doi.org/10.1016/j.snb.2015.07.031
Thanks to Dr. Alejandro Dorazco from CCIQS for asking me to join him in this project which currently includes some other join ventures in the realm of molecular recognition.
New paper in JPC-A
As we approach to the end of another year, and with that the time where my office becomes covered with post-it notes so as to find my way back into work after the holidays, we celebrate another paper published! This time at the Journal of Physical Chemistry A as a follow up to this other paper published last year on JPC-C. Back then we reported the development of a selective sensor for Hg(II); this sensor consisted on 1-amino-8-naphthol-3,6-disulphonic acid (H-Acid) covalently bound to a modified silica SBA-15 surface. H-Acid is fluorescent and we took advantage of the fact that, when in the presence of Hg(II) in aqueous media, its fluorescence is quenched but not with other ions, even with closely related ions such as Zn(II) and Cd(II). In this new report we delve into the electronic reasons behind the quenching process by calculating the most important electronic transitions with the framework laid by the Time Dependent Density Functional Theory (TD-DFT) at the PBE0/cc-pVQZ level of theory (we also included an electron core potential on the heavy metal atoms in order to decrease the time of each calculation). One of the things I personally liked about this work is the combination of different techniques that were used to assess the photochemical phenomenon at hand; some of those techniques included calculation of various bond orders (Mayer, Fuzzy, Wiberg, delocalization indexes), time dependent DFT and charge transfer delocalizations. Although we calculated all these various different descriptors to account for changes in the electronic structure of the ligand which lead to the fluorescence quenching, only delocalization indexes as calculated with QTAIM were used to draw conclusion, while the rest are collected in the SI section.
Thanks a lot to my good friend and collaborator Dr. Pezhman Zarabadi-Poor for all his work, interest and insight into the rationalization of this phenomenon. This is our second paper published together. By the way, if any of you readers is aware of a way to finance a postdoc stay for Pezhman here at our lab, please send us a message because right now funding is scarce and we’d love to keep bringing you many more interesting papers.
For our research group this was the fourth paper published during 2014. We can only hope (and work hard) to have at least five next year without compromising their quality. I’m setting the goal to be 6 papers; we’ll see in a year if we delivered or not.
I’d like to also take this opportunity to thank all the readers of this little blog of mine for your visits and your live demonstrations of appreciation at various local and global meetings such as the ACS meeting in San Francisco and WATOC14 in Chile, it means a lot to me to know that the things I write are read; if I were to make any New Year’s resolutions it would be to reply quicker to questions posted because if you took the time to write I should take the time to reply.
I wish you all the best for 2015 in and out of the lab!
New paper in JACS
Well, I only contributed with the theoretical section by doing electronic structure calculations, so it isn’t really a paper we can ascribe to this particular lab, however it is really nice to see my name in JACS along such a prominent researcher as Prof. Chad Mirkin from Northwestern University, in a work closely related to my area of research interest as macrocyclic recognition agents.
In this manuscript, a calix[4]arene is allosterically opened and closed reversibly by coordinating different kinds of ligands to a platinum center linked to the macrocycle. (This approach has been referred to as the weak link approach.) I recently visited Northwestern and had a great time with José Mendez-Arroyo, the first author, who showed me around and opened the possibility for further work between our research groups.
Closed, semi-open and fully open conformations; selectivity is modulated through cavity size. (Ligands: Green = Chloride; Blue = Cyanide)
Here at UNAM we calculated the interaction energies for the two guests that were successfully inserted into the cavity: N-methyl-pyridinium (Eint = 57.4 kcal/mol) and Pyridine-N-oxide (Eint = +200.0 kcal/mol). Below you can see the electrostatic potential mapped onto the electron density isosurface for one of the adducts. Relative orientation of the hosts within the cavity follows the expected (anti-) alignment of mutual dipole moments. At this level of theory, we could easily be inclined to assert that the most stable interaction is indeed the one from the semi-open compound and that this in turn is due to the fact that host and guest are packed closer together but there is also an orbital issue: Pyridine Oxide is a better electron acceptor than N-Me-pyridinium and when we take a closer look to the (Natural Bonding) orbitals interacting it becomes evident that a closer location does not necessarily yields a stronger interaction when the electron accepting power of the ligand is weaker (which is, in my opinion, both logic and at the same time a bit counterintuitive, yet fascinating, nonetheless).
Electrostatic potential mapped onto the electron density surface of one of the adducts under study
All calculations were performed at the B97D/LANL2DZ level of theory with the use of Gaussian09 and NBO3.1 as provided within the former. Computing time at UNAM’s supercomputer known as ‘Miztli‘ is fully acknowledged.
The full citation follows:
A Multi-State, Allosterically-Regulated Molecular Receptor With Switchable Selectivity
Jose Mendez-Arroyo †, Joaquín Barroso-Flores §,Alejo M. Lifschitz †, Amy A. Sarjeant †, Charlotte L. Stern †, and Chad A. Mirkin *†
Thanks to José Mendez-Arroyo for contacting me and giving me the opportunity to collaborate with his research; I’m sure this is the first of many joint projects that will mutually benefit our groups.
New paper in Computational and Theoretical Chemistry
I always get very happy to have a new paper out there! I find it exciting but most of all liberating since it makes you feel like your work is going somewhere but most of all that it is making its way ‘out there’; there is a strong feeling of validation, I guess.
Two very different families of calix[n]arenes (Fig 1) were tested as drug carriers for a very small molecule with a huge potential as a chemotherapeutic agent against Leukemia, namely, 3-phenyl-1H-[1]benzofuro[3,2-c]pyrazole a.k.a. GTP which has proven to be an effective in vitro Tyrosine Kinase III inhibitor. Having such a low molecular weight it is expected to have a very high excretion rate therefore the use of a carrier could increase its retention time and hence its activity. This time we considered n = 4, 5, 6 and 8 for the size of the cavities and R = -SO3H and -OEt as functional groups on the upper rim as to evaluate only a polar coordinating group and a non-polar non-coordinating one since GTP offers two H-bond acceptor sites and one H-bond donor one along the π electron density that could form π – π stacking interactions between the aromatic groups on GTP and the walls of the calixarene.
Fig 1. Calixarenes under study and their complexes with GTP
Once again calculations were carried out at the B97D/6-31G(d,p) level of theory along with molecular dynamics simulations for over 100 ns of production runs. NBO Deletion interaction energies were computed in order to discern which hosts formed the most stable complexes.
NBO Del interaction energies B97D/6-31G(d,p)
You may find a link to the ScienceDirect website for downloading the paper from this link. Last, but certainly not least, I’d like to thank all coauthors for their contributions and patience in getting this study published: Dr. Rodrigo Galindo-Murillo; Alberto Olmedo-Romero; Eduardo Cruz-Flores; Dr. Petronela M. Petrar and Prof. Dr. Kunsági-Máté Sándor. Thanks a lot for everything!
Donor and acceptor H-bond sites increases the probability of keeping the drug in place for a higher retention rate
New paper in Journal of Chemical Theory and Computation
Happy new year to all my readers!
Having a new paper published is always a matter of happiness for this computational chemist but this time I’m excedingly excited about anouncing the publishing of a paper in the Journal of Chemical Theory and Computation, which is my highest ranked publication so far! It also establishes the consolidation of our research group at CCIQS as a solid and competitive group within the field of theoretical and computational chemistry. The title of our paper is “In Silico design of monomolecular drug carriers for the tyrosine kinase inhibitor drug Imatinib based on calix- and thiacalix[n]arene host molecules. A DFT and Molecular Dynamics study“.
In this article we aimed towards finding a suitable (thia-) calix[n]arene based drug delivery agent for the drug Imatinib (Gleevec by Novartis), which is a broadly used powerful Tyrosine Kinase III inhibitor used in the treatment of Chronic Myeloid Leukaemia and, to a lesser extent, Gastrointestinal Stromal Tumors; although Imatinib (IMB) exhibits a bioavailability close to 90% most of it is excreted, becomes bound to serum proteins or gets accumulated in other tissues such as the heart causing several undesired side effects which ultimately limit its use. By using a molecular capsule we can increase the molecular weight of the drug thus increasing its retention, and at the same time we can prevent Imatinib to bind, in its active form, to undesired proteins.
We suggested 36 different calix and thia-calix[n]arenes (CX) as possible candidates; IMB-CX complexes were manually docked and then optimized at the B97D/6-31G(d,p) level of theory; Stephan Grimme’s B97D functional was selected for its inclusion of dispersion terms, so important in describing π-π interactions. Intermolecular interaction energies were calculated under the Natural Bond Order approximation; a stable complex was needed but a too stable complex would never deliver its drug payload! This brings us to the next part of the study. A monomolecular drug delivery agent must be able to form a stable complex with the drug but it must also be able to release it. Molecular Dynamics simulations (+100 ns) and umbrella sampling methods were used to analyse the release of the drug into the aqueous media.
Optimized geometries for the 20 most stable complexes under study (B97D/6-31G*)
Potential Mean Force profiles for the four most stable complexes for position N1 and N2 from the QM simulations are shown below (Red, complexes in the N1 position, blue, N2 position). These plots, derived from the MD simulations give us an idea of the final destination of the drug respect of the calixarene carrier. In the next image, the three preferred structures (rotaxane-like; inside; released) for the final outcome of the delivery process are shown. The stability of the complexes was also assessed by calculating the values of ΔG binding through the use of the Poisson equations.
PMF for the most stable compounds
General MD simulation final structures
Thanks to my co-authors Maria Eugenia Sandoval-Salinas and Dr. Rodrigo Galindo-Murillo for their enormous contributions to this work; without their hard work and commitment to the project this paper wouldn’t have been possible.
