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Calculation of Intermolecular Interactions for Sensors with Biological Applications


Two new papers on the development of chemosensors for different applications were recently published and we had the opportunity to participate in both with the calculation of electronic interactions.

A chemosensor requires to have a measurable response and calculating either that response from first principles based on the electronic structure, or calculating another physicochemical property related to the response are useful strategies in their molecular design. Additionally, electronic structure calculations helps us unveil the molecular mechanisms underlying their response and efficiency, as well as providing a starting point for their continuous improvement.

In the first paper, CdTe Quantum Dots (QD’s) are used to visualize in real time cell-membrane damages through a Gd Schiff base sensitizer (GdQDs). This probe interacts preferentially with a specific sequence motif of NHE-RF2 scaffold protein which is exposed during cell damage. This interactions yields intensely fluorescent droplets which can be visualized in real time with standard instrumentation. Calculations at the level of theory M06-2X/LANL2DZ plus an external double zeta quality basis set on Gd, were employed to characterize the electronic structure of the Gd³⁺ complex, the Quantum Dot and their mutual interactions. The first challenge was to come up with the right multiplicity for Gd³⁺ (an f⁷ ion) for which we had no experimental evidence of their magnetic properties. From searching the literature and talking to my good friend, inorganic chemist Dr. Vojtech Jancik it was more or less clear the multiplicity had to be an octuplet (all seven electrons unpaired).

As can be seen in figure 1a the Gd-N interactions are mostly electrostatic in nature, a fact that is also reflected in the Wiberg bond indexes calculated as 0.16, 0.17 and 0.21 (a single bond would yield a WBI value closer to 1.0).

PM6 optimizations were employed in optimizing the GdQD as a whole (figure 1f) and the MM-UFF to characterize their union to a peptide sequence (figure 2) from which we observed somewhat unsurprisingly that Gd³⁺interacts preferently with the electron rich residues.

This research was published in ACS Applied Materials and Interfaces. Thanks to Prof. Vojtech Adam from the Mendel University in Brno, Czech Republic for inviting me to collaborate with their interdisciplinary team.

The second sensor I want to write about today is a more closer to home collaboration with Dr. Alejandro Dorazco who developed a fluorescent porphyrin system that becomes chiefly quenched in the presence of Iodide but not with any other halide. This allows for a fast detection of iodide anions, related to some gland diseases, in aqueous samples such as urine. This probe was also granted a patent which technically lists yours-truly as an inventor, cool!

The calculated interaction energy was huge between I⁻ and the porphyrine, which supports the idea of a ionic interaction through which charge transfer interactions quenches the fluorescence of the probe. Figure 3 above shows how the HOMO largely resides on the iodide whereas the LUMO is located on the pi electron system of the porphyrine.

This research was published in Sensors and Actuators B – Chemical.

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Mg²⁺ Needs a 5th Coordination in Chlorophylls – New paper in IJQC


Photosynthesis, the basis of life on Earth, is based on the capacity a living organism has of capturing solar energy and transform it into chemical energy through the synthesis of macromolecules like carbohydrates. Despite the fact that most of the molecular processes present in most photosynthetic organisms (plants, algae and even some bacteria) are well described, the mechanism of energy transference from the light harvesting molecules to the reaction centers are not entirely known. Therefore, in our lab we have set ourselves to study the possibility of some excitonic transference mechanisms between pigments (chlorophyll and its corresponding derivatives). It is widely known that the photophysical properties of chlorophylls and their derivatives stem from the electronic structure of the porphyrin and it is modulated by the presence of Mg but its not this ion the one that undergoes the main electronic transitions; also, we know that Mg almost never lies in the same plane as the porphyrin macrocycle because it bears a fifth coordination whether to another pigment or to a protein that keeps it in place (Figure 1).

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Figure 1 The UV-Vis spectra of BCHl-a changes with the coordination state

During our calculations of the electronic structure of the pigments (Bacteriochlorophyll-a, BChl-a) present in the Fenna-Matthews-Olson complex of sulfur dependent bacteria we found that the Mg²⁺ ion at the center of one of these pigments could in fact create an intermolecular interaction with the C=C double bond in the phytol fragment which lied beneath the porphyrin ring.

fig3

Figure 2 Mg points ‘downwards’ upon optimization, hinting to the interaction under study

 

This would be the first time that a dihapto coordination is suggested to occur in any chlorophyll and that on itself is interesting enough but we took it further and calculated the photophysical implications of having this fifth intramolecular dihapto coordination as opposed to a protein or none for that matter. Figure 3 shows that the calculated UV-Vis spectra (calculated with Time Dependent DFT at the CAM-B3LYP functional and the cc-pVDZ, 6-31G(d,p) and 6-31+G(d,p) basis sets). A red shift is observed for the planar configuration, respect to the five coordinated species (regardless of whether it is to histidine or to the C=C double bond in the phytyl moiety).

 

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Figure 3 CAMB3LYP UV-VIS spectra. Basis set left to right cc-PVDZ, 6-31G(d,p) and 6-31+G(d,p)

Before calculating the UV-Vis spectra, we had to unambiguously define the presence of this observed interaction. To that end we calculated to a first approximation the C-Mg Wiberg bond indexes at the CAM-B3LYP/cc-pVDZ level of theory. Both values were C(1)-Mg 0.022 and C(2)-Mg 0.032, which are indicative of weak interactions; but to take it even further we performed a non-covalent interactions analysis (NCI) under the Atoms in Molecules formalism, calculated at the M062X density which yielded the presence of the expected critical points for the η²Mg-(C=C) interaction. As a control calculation we performed the same calculation for Magnoscene just to unambiguously assign these kind of interactions (Fig 4, bottom).

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Figure 4 (a), (b) NCI analysis for Mg-(C=C) interaction compared to Magnesocene (c)

This research is now available at the International Journal of Quantum Chemistry. A big shoutout and kudos to Gustavo “Gus” Mondragón for his work in this project during his masters; many more things come to him and our group in this and other research ventures.

I’m done with Computational Studies


I’ve lately reviewed a ton of papers whose titles begin with some version of “Computational studies of…“, “Theoretical studies of…” or even more subtly just subtitled “A theoretical/computational study” and even when I gotta confess this is probably something I’ve done once or twice myself, it got me thinking about the place and role of computational chemistry within chemistry itself.

As opposed to physicists, chemists are pressed to defend a utilitarian view of their work and possibly because of that view some computational chemists sometimes lose sight of their real contribution to a study, which is far from just performing a routine electronic structure calculation. I personally don’t like it when an experimental colleague comes asking for ‘some calculations’ without a clear question to be answered by them; Computational Chemistry is not an auxiliary science but a branch of physical chemistry in its own right, one that provides all the insight experiments -chemical or physical- sometimes cannot.

I’m no authority on authoring research papers but I encourage my students to think about the titles of their manuscripts in terms of what the manuscript most heavily relies on; whether it’s the phenomenon, the methodology or the object of the study, that should be further stressed on the title. Papers titled “Computational studies of…” usually are followed by ‘the object of study’ possibly overlooking the phenomenon observed throughout such studies. It is therefore a disservice to the science contained within the manuscript, just like experimental papers gain little from titles such as “Synthesis and Characterization of…“. It all comes down to finding a suitable narrative for our work, something that I constantly remind my students. It’s not about losing rigor or finding a way to oversell our results but instead to actually drive a point home. What did you do why and how. Anna Clemens, a professional scientific writer has a fantastic post on her blog about it and does it far better than I ever could. Also, when ranting on Twitter, the book Houston, we have a narrative was recommended to me, I will surely put it my to-read list.

While I’m on the topic of narratives in science, I’m sure Dr. Stuart Cantrill from Nature Chemistry wouldn’t mind if I share with you his deconstruction of an abstract. Let’s play a game and give this abstract a title in the comments section based on the information vested in it.DcJCrr_W0AQCNQZ

A new paper on the Weak Link Approach


Chemically actuating a molecule is a very cool thing to do and the Weak Link Approach (WLA) allows us to do precisely that through the reversible coordination of one or various organometallic centers to a longer ligand that opens or closes a macrocyclic cavity. All this leads to an allosteric effect so important in biological instances available in inorganic molecules. Once again, the Mirkin group at Nortwestern University in Evanston, Illinois, has given me the opportunity to contribute with the calculations to the energetic properties of these actuators as well as their electronic properties for their use as molecular scavengers or selective capsules for various purposes such as drug delivery agents.

As in the previous WLA work (full paper), the NBODel procedure was used at the B97D/LANL2DZ level of theory, only this time the macrocycle consisted of two organometallic centers and for the first time the asymmetric opening of the cavity was achieved, as observed by NMR. With the given fragments, all possibilities shown in scheme 1 were obtained. The calculated bond energies for the Pt – S bonds are around 60 – 70 kcal/mol whereas for the Pt – Cl bonds the values are closer to 90 kcal/mol. This allows for a selective opening of the cavity which can then be closed by removing the chlorine atoms with the help of silver salts.

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For the case of complex mixture 4a, 4b, and 4c, the thermochemistry calculations show they are all basically isoenergetic with differences in the thousandths of kcal/mol. The possibilities for the groups in the weakly bonded ligands are enormous; currently, there is work being done about substituting those phenyl rings for calix[4]arenes in order to have a macrucyclic capsule made by macrocylic capusules.

Thanks to Andrea D’Aquino for taking me into her project, for all the stimulating discussions and her great ideas for expanding WLA into new avenues; I’m sure she’ll succeed in surprising us with more possibilities for these allosteric macrocycles.

The full paper is published in Inorganic Chemistry from the ACS (DOI: 10.1021/acs.inorgchem.7b02745). Thanks for reading and -if you made it this far into the post- happy new year!

The Evolution of Photosynthesis


Recently, the journal ACS Central Science asked me to write a viewpoint for their First Reactions section about a research article by Prof. Alán Aspuru-Guzik from Harvard University on the evolution of the Fenna-Matthews-Olson (FMO) complex. It was a very rewarding experience to write this piece since we are very close to having our own work on FMO published as well (stay tuned!). The FMO complex remains a great research opportunity for understanding photosynthesis and thus the origin of life itself.

In said article, Aspuru-Guzik’s team climbed their way up a computationally generated phylogenetic tree for the FMO from different green sulfur bacteria by creating small successive mutations on the protein at a time while also calculating their photochemical properties. The idea is pretty simple and brilliant: perform a series of “educated guesses” on the structure of FMO’s ancestors (there are no fossil records of FMO so this ‘educated guesses’ are the next best thing) and find at what point the photochemistry goes awry. In the end the question is which led the way? did the photochemistry led the way of the evolution of FMO or did the evolution of FMO led to improved photochemistry?

Since both the article and viewpoint are both published as open access by the ACS, I wont take too much space here re-writing the whole thing and will instead exhort you to read them both.

Thanks for doing so!

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

Imagen1

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’

Imagen2.jpg

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.

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

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)

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!

fig8

Donor and acceptor H-bond sites increases the probability of keeping the drug in place for a higher retention rate

Donor and acceptor H-bond sites increases the probability of keeping the drug in place for a higher retention rate

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