Category Archives: Articles
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.
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.
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.
Having a new paper out is always fun and this week we got the wonderful news from the Journal of Physical Chemistry C that a paper I co authored with Prof. Alireza Badiei at the University of Tehran in Iran and his student, who actually got us all in touch, Dr. Pezhman Zarabadi-Poor, was accepted for publication.
The paper is titled “Selective Optical Sensing of Hg(II) in Aqueous Media by H-Acid/SBA-15: A Combined Experimental and Theoretical Study“; in it we explored the fluorescence quenching mechanism for a Hg(II) complex which forms the basis of a novel selective mercury detector. Geometry optimizations were carried out at the PBE0/6-31++G** PCM level of theory (along with the aug-cc-pVDZ-PP basis set and corresponding ECP for Hg), also the electronic spectrum of both the free acid and the Hg(II) complex was calculated.
(Frontier orbitals were depicted using Chemcraft)
We can observe that HOMO and LUMO+1 are mainly located on the naphtalene ring allowing for the S0 -> S1 transition and back, which accounts for the molecular fluorescence. Other internal conversion processes were also assessed and discussed in the paper which accounts for the quenching effect. In short, we have obtained a full quantum description of the mechanism by which coordination of the free acid to Hg(II) alters the ligand’s electronic structure converting its emisive lowest-lying excited state to a dark state, i.e., quenching! Pretty cool stuff!
Once again thanks to both Dr. Zarabadi-Poor and Prof. Badiei for thinking about me for collaborating with them in this joint endeavor which hopefully wont be our last. A PDF copy of the article is available by direct request through this post.
Thanks for reading, sharing, rating and commenting.
Here is a link to an article I was invited to write by my good old friend, Dr. Eddie López-Honorato from CINVESTAV – Saltillo; Mexico, for the latest issue of the journal ‘Ciencia y Desarrollo’ (Science and Development) to which he was a guest editor. ‘Ciencia y Desarrollo’ is a popular science magazine edited by the National Council for Science and Technology (CONACyT) of which I’ve blogged before.
This magazine is intended for people interested in science with a general knowledge of it but not necessarily specialized in any field. With that in mind, I decided to write about the power of computational chemistry in predicting some phenomena while shedding light in certain aspects of chemistry that are not that readily available through experiments. The article is titled ‘Chemistry without flasks: Simulating chemical reactions‘. The link will take you to the magazine’s website which is in Spanish, as is the article itself, and only to the first page; so, below I translated the piece for anyone who could be interested in reading it (Hope I’m not infringing any copyright laws!). Don’t forget to also check out Dr. López-Honorato’s blog on nuclear energy research and the development of materials for nuclear waste containment! Encourage him to blog more often by liking and following his blog.
Chemistry without flasks?
Typically we think of a chemist as a scientist who, dressed in a white robe and protected with safety glasses and latex gloves, busily working within a laboratory, surrounded by measurement equipment, glassware and bottles with colored substances; pours one substance onto other substance, transforming them into new substances while noting that the chemical reaction occurs through color changes, heat release , perhaps gas, and occasionally even an explosion.
Thus chemistry, the study of the material processing involves active experimentation to accomplish chemical reactions subsequently confirmed, although indirectly, that the changes have been conducted in the microscopic world, moreover, in the molecular and atomic world. The chemist plans these changes based on the knowledge he has of the chemical properties of the substances of which he started and, like any other substance, are due to its molecular structure, i.e., the spatial arrangement of the atoms that form it.
Under this archetypal image just posed, then it’s at least funny to think that there is a branch of chemistry named Theoretical Chemistry.
What is theoretical chemistry?
Theoretical chemistry is a kind of bridge between chemistry and physics; using laws and equations that govern the subatomic world, to calculate the molecular structure of a substance, more specifically calculate the distribution of electrons surrounding the molecule forming a cloud, which interact with the electron cloud of another molecule to form a new substance. It is based on the knowledge of the electron density cloud or we can understand and predict the chemical properties of any substance. We can then define theoretical chemistry as the set of physical theories that describe the distribution and properties of the electron cloud belonging to a molecule, in this particular mathematical description we call electronic structure and this is the starting point for descriptions and chemical predictions.
What is it good for?
Through theoretical chemistry we can find answers to fundamental questions about the structure of matter. Consider a molecule of water, which has the chemical formula H2O. This formula implies that there are two hydrogen atoms attached to an oxygen atom But what spacial structure does a water molecule have? The simplest geometry it could take would be a linear structure, in which the angle formed by the three atoms is 180 °. However, the water molecule has an angle of 109 °, far from a linear structure. In Figure 2 we can see the result of the calculation of the electronic structure of H2O, it observed that the electron cloud that exists on the oxygen atom also has a place in space and thus push the hydrogen atoms bringing them together instead of allowing them to take a more comfortable conformation.
Figure 2. Oxygen remaining electrons (red cloud around the oxygen atom) that are not chemically push the hydrogen atoms towards each other.
The industrial area currently impacted by the application of theoretical chemistry is the pharmacist, as they generate a new drug involves significant investment in financial and human resources, so predicting the properties of a molecule with pharmacological activity before synthesizing is highly attractive. Therefore it has been generated within the theoretical chemistry field, otherwise known as branch Rational Drug Design.
Drugs acting on our organism when active molecules interact directly with the various proteins which are distributed in the tissue cells. If the structure of the protein is known and we attack is known also a drug which acts on it, then we can design similar drugs having greater efficacy in the treatment of diseases. But it is not only fit one molecule to another, but to calculate the energy of interaction, the energy of dissolution and the probability that this interaction can be observed experimentally (Figure 3). The calculation of the interaction energy between the drug and the protein tells how strongly attract each other, a weak attraction drug will result in a low efficiency, while a greater attraction involve a more effective drug.
How do you calculate a molecule?
All matter exists in the universe is made of atoms, which in turn are composed of a nucleus of protons and neutrons surrounded by a cloud of electrons. When two or more atoms combine to form a molecule combining do their electron clouds and how do these combinations are best described by the equations of quantum mechanics, the branch of physics that describes the behavior of the subatomic world. However, due to its complexity, the equations of quantum mechanics can only be accurately resolved in the simplest cases such as the hydrogen atom, which consists of a single electron orbiting a proton. We must therefore resort to a range of methods and approaches to tackle cases of chemical interest and even biological.
For years the only available computers could solve the approximate equations for small molecules, no later than thirty atoms, which which can be interesting, but not entirely useful. Today modern supercomputing equipment (which may amount to up to tens or even hundreds of powerful computers connected together to work cooperatively) allow us to make models with hundreds of atoms molecules such as proteins or DNA fragments.
While the software available to perform these calculations is developed continuously for the last thirty years has been the progress in the design of computer systems able to perform thousands of operations per second the cornerstone that has made the theoretical chemistry a predictive tool commonly used. Today the branch known as Molecular Dynamics, which studies the interactions between molecules over time, has benefited from the development of the latest game consoles, as their processors, known as graphics processing units (GPUs , for its acronym in English) are able to perform calculations in parallel: Many of the images seen in our video games are actually calculated, not animated, this means that the console must calculate how to answer each item on the screen According to each stimulus we introduce. Conversely, if the images were animated, the answers would be always the same and the game would become unrealistic. Each game event should be calculated almost immediately to maintain its fluidity and emotion, in such a way that these GPUs have to be able to perform several mathematical operations simultaneously.
Traditionally molecular dynamics is based on the equations of classical physics, which only see the time evolution of molecules like solid objects collide, hundreds of molecules floating in water or other solvent. With the advent of GPUs can include dynamic calculating the electronic structure so we can peek into biological processes such as DNA replication or the passage of nutrients through a channel protein embedded in the membrane of a cell.
Since the fundamental understanding of the distribution of electrons in a molecule, its structure and properties to rational drug design, new materials based on molecular modeling theoretical chemistry is a powerful tool which is constantly progressing. The development of computer systems increasingly powerful detail allows us to meet the electronic processes involved in a chemical reaction while we can predict the real-time progress of molecular transformations. All this brings us ever closer to the dream of modern alchemists: transform matter to obtain substances with properties designed to pleasure.
In the nineteenth century, the American philosopher Ralph Waldo Emerson, wrote: “Chemistry was born from the dream of the alchemists to turn cheap metals into gold. By failing to do so, they have accomplished much more important things. ” And yes. Today we delve into the innermost secrets of nature not only to understand how it works but also to modify its operation on our behalf.
I don’t know why I haven’t written about the Local Bond Order (LBO) before! And a few days ago when I thought about it my immediate reaction was to shy away from it since it would constitute a blatant self-promotion attempt; but hell! this is my blog! A place I’ve created for my blatant self-promotion! So without further ado, I hereby present to you one of my own original contributions to Theoretical Chemistry.
During the course of my graduate years I grew interested in weakly bonded inorganic systems, namely those with secondary interactions in bidentate ligands such as xanthates, dithiocarboxylates, dithiocarbamates and so on. Description of the resulting geometries around the central metallic atom involved the invocation of secondary interactions defined purely by geometrical parameters (Alcock, 1972) in which these were defined as present if the interatomic distance was longer than the sum of their covalent radii and yet smaller than the sum of their van der Waals radii. This definition is subject to a lot of constrictions such as the accuracy of the measurement, which in turn is related to the quality of the monocrystal used in the X-ray difraction experiment; the used definition of covalent radii (Pauling, Bondi, etc.); and most importantly, it doesn’t shed light on the roles of crystal packing, intermolecular contacts, and the energetics of the interaction.
This is why in 2004 we developed a simple yet useful definition of bond order which could account for a single molecule in vacuo the strength and relevance of the secondary interaction, relative to the well defined covalent bonds.
Barroso-Flores, J. et al. Journal of Organometallic Chemistry 689 (2004) 2096–2102 http://dx.doi.org/10.1016/j.jorganchem.2004.03.035,
Let a Molecular Orbital be defined as a wavefunction ψi which in turn may be constructed by a linear combination of Atomic Orbitals (or atom centered basis set functions) φj
We define ζLBO in the following way, where we explicitly take into account a doubly occupied orbital (hence the multiplication by 2) and therefore we are assuming a closed shell configuration in the Restricted formalism.
The summation is carried over all the orbitals which belong to atom A1 and those of atom A2.
Simplifying we yield,
where Sjk is the overlap integral for the φj and φk functions.
By summing over all i MOs we have accomplished with this definition to project all the MO’s onto the space of those functions centered on atoms A1 and A2. This definition is purely quantum mechanical in nature and is independent from any geometric requirement of such interacting atoms (i.e. interatomic distance) thus can be used as a complement to the internuclear distance argument to assess the interaction between them. This definition also results very simple and easy to calculate for all you need are the coefficients to the LCAO expansion and the respective overlap integrals.
Unfortunately, the Local Bond Order hasn’t found much echo, partly due to the fact that it is hidden in a missapropriate journal. I hope someone finds it interesting and useful; if so, don’t forget to cite it appropriately ;-)
We recently got notice of our paper being accepted for publication in the Journal of Inclusion Phenomena and Macrocyclic Chemistry. We are very pleased with this news! The paper’s title is “Ab initio calculations of electronic interactions in inclusion complexes of calix- and thiacalix[n]arenes and block s cations” and is being co-authored by Dr. Petronela Petrar, Prof. Dr. Kunsagi-Mate Sandor, the late Prof. Dr. Ioan Silaghi-Dumitrescu and yours truly. Most of the work reported in this article was performed at the Faculty of Chemistry of the Babeş-Bolyai University in Romania and also at Pécsi Tudomanyegyetem in Hungary (one lovely summer that was!)
In this paper we address the calculations of the cavity of a small family of calixarenes and explore the electrostatic interactions present when some s block cations are inserted within. Two main factors affect the stability of the complexes: Fitting. The ratio between the cation radius and the mean size of the cavity; The second factor is the ionic-π interactions with the aromatic rings that make the cavity.
As usual the paper is available in pdf format at your request from this author.
Barroso-Flores, Joaquín; Silaghi-Dumitrescu, Ioan; Petrar, P. M.; Kunsagi-Mate, Sandor* Ab initio calculations of electronic interactions in inclusion complexes of calix- and
thiacalix[n]arenes and block s cations J. Incl. Phenomena April 2012
A new paper is coming out! These are always good news for someone whose productivity is evaluated by the number of his/her publications, and in my case the pleasure is double. It turns out that despite the fact a scientist is continuously working, there isn’t always the possibility of having results put “out there”. Back in Mexico we have the “National Researchers System” in which the National Council for Science and Technology encourages us to keep on working by providing economical stimuli and evaluating our productivity by, yes, the number of papers published each year. For three years I worked for a private research center in which fundamental science was tackled as far as it was economically possible and cost effective. Practically all of the work carried out there was confidential since the company it belonged to is leader in its market, not only in Mexico but in Latin America and southern USA! At this facility some papers were published from time to time (most of them came from research in molecular modeling) but not without struggle against the administrators. We can thank for most of the struggle (and the papers!) to Dr. Armando Gama-Goicochea, a great physicist as well as a great friend of mine.
Anyway, the bottom line here is that I’m excited about having a new paper coming out again, even if I’m nowhere close to being first author. This three year paper fastening seems to be over and let us hope it’s only the first of various now that I’m holding a postdoc position here in Romania.
In this paper we tackled the bonding properties of some Aluminum complexes with three chalcogeno triazoles. The electrostatic potential mapped onto a density surface of one of those compounds is currently shown in the header of this blog, btw. We concluded that the bonding in such compounds is mainly covalent as opposed to the more conventional electrostatic notion prevailing for such hard atoms. In order to get this information we resorted to Natural Bonding Analysis calculations with the RHF method and somewhat large basis sets in order to get a full description of the electronic density.
I very much like these systems in which several bonding possibilities occur. The fact that nature is chosing one out of many has always a reason which can be assessed by our models and may serve us to learn how to modify it’s behaviour.
Coordination Diversity of Aluminum Centers Molded by Triazole Based Chalcogen Ligands
Jocelyn Alcántara-García, Vojtech Jancik, Joaquín Barroso, Sandra Hidalgo-Bonilla, Raymundo Cea-Olivares, Rubén A. Toscano and Mónica Moya-Cabrera