Category Archives: Research

Women in #CompChem and the rest of STEM


In the past I’ve avoided this topic for various reasons. First, because I strongly believe that focusing on labels perpetuates them, and as scientists, we should always rise above them, for is science and not scientists what’s important. I remember my former PhD advisor, Prof. Cogordan, saying that “Liberties are exercised, not demanded“. Take Rosa Parks, for instance, her refusal to move to the back of the bus was an exercise of her liberty, and one that moved to a profound change, alas not without turmoil. But should I really call it a label? since it applies to roughly half the potential brain power available in the planet it then becomes a relevant question. Are equality and political correctness mutually exclusive terms?

It could be argued that I talk from a privileged position being a male scientist but since I’m a Mexican, non-white, non-US-based, male scientist those privileges are only so many.

I first began drafting this post way back before November 2016, when the misogyny displayed by a presidential candidate was in everyone’s mind to such a large extent that even when it even seemed prone to cause his demise it didn’t. The women’s march in D.C. has proven the topic to be still quite relevant though, and next April 22nd, Earth Day, a scientists march will take place to protest against policies that put science -and therefore mankind- in jeopardy. Some particular issues associated with the march will be the communication gag orders against scientific federal agencies; the consequences of the travel-ban to scientists from black-listed countries and, of course, the threat of having a misogynistic environment on the status of women in STEM careers.

Fact: There is a clear selection bias since there is still a large number disparity between men and women in academia throughout the world and since the number of academic position is growing at a much lower rate than the number of scientists competing for such positions, the race has become tighter and usually women take the worst part of the deal. There is a leaking pipeline in which women don’t reach the end of the race. I imagine in some cases it may have to do with maternity as it is still conservatively perceived by most countries but issues like harassment and condescension are not to be ignored.
Fact: Scientific curiosity is innate to all human beings -which confirms the above mentioned bias- therefore talking about encouraging young women to pursuit a career in STEM is plain stupid; they don’t need to be encouraged they must stop being discouraged somewhere along the path. The playing field for both genders should be leveled or science risks loosing half the population in these dire times in which all the brain power available is much needed. Also, I fear the continuous talk about these disadvantages could be off-putting for future generations of women who might be interested in undertaking STEM careers. Leveling the field for female and male scientists should be done and not just demanded but details about the mechanisms to accomplish it are still unclear and vary from one institution to another. Here in Mexico, for instance, all public universities have collective contracts, therefore every scientist in a given level earns as much as another in the same level. In other countries salaries are personally negotiated and therefore each scientists earnings vary, which has led to women earning less on average. Now, the ease with which levels are climbed within an institution are also a matter for debate. Does this mean that earnings and positions are the main problems women face in academia? Could they be the best starting points? Is the rate of enrollment the root of the problem? If so, are us teachers and professors to blame?

Another reason why I avoided this topic was because it would seem so patronizing on my part to give a shout-out to women whose work in computational chemistry I so much admire when I myself could only aspire to one day have work of their quality. They definitely don’t need my praises because they have well earned all our admiration. Nonetheless, here is a link to a great directory of women working in computational chemistry in which some great names are found such as Anna Krylov, Gloria Tabacchi, Romelia Salomón, Patricia Hunt, and so many more great scientists from all over the world. Here in Mexico we count with names such as Margarita Bernal, Patrizia Calaminici, Annia Galano, Estela Mayoral and so many other. It is hard to make a comprehensive list, and as I said before I could only aspire to have work with the same quality as theirs. The importance of recognizing and promoting women to take a career in computational chemistry will in short be addressed by the FemEx-NL-2017 conference next June 22nd in the Netherlands; their motto is “Promoting female excellence in theoretical and computational chemistry”, certainly a worthy and noble endeavor for a problem far from solved.  

Perhaps another good reason for writing this post lies in the image below. It is a true statement but we should analyze the causality for it and fix whatever it is we’re doing wrong because it is certainly not the plumbing:

I have a daughter. I want her to be able to do whatever she wants when she grows up without deterrence from unfairness. I want a world for her without labels so she never has the option of playing ‘The Woman Card’. It wouldn’t be fair for anyone around her.

This wont be the last post on this topic. Please share your views in the comments and criticism section. They are all welcome.

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The ‘art’ of finding Transition States Part 1


Guillermo CaballeroGuillermo Caballero, a graduate student from this lab, has written this two-part post on the nuances to be considered when searching for transition states in the theoretical assessment of reaction mechanisms. He’s been quite successful in getting beautiful energy profiles for organic reaction mechanisms, some of which have even explained why some reactions do not occur! A paper in Tetrahedron has just been accepted but we’ll talk about it in another post. I wanted Guillermo to share his insight into this hard practice of computational chemistry so he wrote the following post. Enjoy!

 

Yes, finding a transition state (TS) can be one of the most challenging tasks in computational chemistry, it requires both a good choice of keywords in your route section and all of your chemical intuition as well. Herein I give you some good tricks when you have to find a transition state using Gaussian 09 Rev. D1

METHOD 1. The first option you should try is to use the opt=qst2 keyword. With this method you provide the structures of your reagents and your products, then the program uses the quadratic synchronous transit algorithm to find a possible transition state structure and then optimize it to a first order saddle point. Here is an example of the input file.

link 0
--blank line--
#p b3lyp/6-31G(d,p) opt=qst2 geom=connectivity freq=noraman
--blank line--
Charge Multiplicity
Coordinates of reagents
--blank line--
Charge Multiplicity
Coordinates of products
--blank line---

It is mandatory that the numbering must be the same in the reagents and the products otherwise the calculation will crash. To verify that the label for a given atom is the same in reagents and products you can go to Edit, then Connection. This opens a new window were you can manually modify the numbering scheme. I suggest you to work in a split window in gaussview so you can see at the same time your reagents and products.

The keyword freq=noraman is used to calculate the frequencies for your optimized structure, it is important because for a TS you must only observe one imaginary frequency, if not, then that is not a TS and you have to use another method. It also occurs that despite you find a first order saddle point, the imaginary frequency does not correspond to the bond forming or bond breaking in your TS, thus, you should use another method. I will give you advice later in the text for when this happens. When you use the noraman in this keyword you are not calculating the Raman frequencies, which for the purpose of a TS is unnecessary and saves computing time. Frequency analysis MUST be performed AT THE VERY SAME LEVEL OF THEORY at which the optimization is performed.

The main advantage for using the qst2 option is that if your calculation is going to crash, it generally crashes at the beginning, in the moment of guessing your transition state structure. Once the program have a guess, it starts the optimization. I suggest you to ask the algorithm to calculate the force constants once, this generally improves on the convergence, it will take slightly more time depending on the size of your structure but it pays off. The keyword in the route section is opt=(qst2,calcfc). Indeed, I hardly encourage you to use the calcfc keyword in any optimization you want to run.

METHOD 2. If method 1 does not work, my next advice is to use the opt=ts keyword. For this method, the coordinates in your input file are those for the TS structure. Here is an example of the input file.

link 0
--blank line--
#p b3lyp/6-31G(d,p) opt=ts geom=connectivity freq=noraman
--blank line--
Charge Multiplicity
Coordinates of TS
--blank line--

The question that arises here is how should I get the coordinates for my TS? Well, honestly this is not a trivial task, here is where you use all the chemistry you know. For example, you can start with the coordinates of your reagents and manually get them closer. If you are forming a bond whose length is to be 1.5Å, then I suggest you to have that length in 1.6Å in your TS. Sometimes this becomes trial and error but the most accurate your TS structure is, based on your chemical knowledge, the easiest to find your TS will be. As another example, if you want to find a TS for a [1,5]-sigmatropic reaction a good TS structure will be putting the hydrogen atom that migrates in the middle point through the way. I have to insist, this method hardly depends on your imagination to elucidate a TS and on your chemistry background.

Most of the time when you use the opt=ts keyword the calculations crashes because of an error in the number of eigenvalues, you can avoid it adding noeigen to the route section; here is an example of the input file, I encourage you to use this method.

link 0
--blank line--
#p b3lyp/6-31G(d,p) opt=(ts,noeigen,calcfc) geom=connectivity freq=noraman
--blank line--
Charge Multiplicity
Coordinates of TS
--blank line--

If you have problems in the optimization steps I suggest you to ask the algorithm to calculate the force constants in every step of the optimization opt=(ts,noeigen,calcall) this is quite a harsh method because will consume long computing time but works well for small molecules and for complicated TSs to find.

Another ‘tricky’ way to get your coordinates for your TS is to run the qst2 calculation, then if it fails, take the second- or the third-step coordinates and used them as a ‘pre-optimized’ set of coordinates for this method.

By the way, here is another useful trick. If you are evaluating a group of TSs, let’s say, if you are varying a functional group among the group, focus on finding the TS for the simplest case, then use this optimized TS as a template where you add the moieties and use this this method. This works pretty well.

For this post we’ll leave it up to here and post the rest of Guillermo’s tricks and advice on finding TS structures next week when we’ll also discuss the use of IRC calculations and some considerations on energy corrections when plotting the full energy profile. In the mean time please take the time to rate, like and share this and other posts.

Thanks for reading!

 

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.

Internal Symposium at CCIQS – 2016 edition


Having a symposium right after the winter holidays is a great way to get back in touch with colleagues and students; we get to hear how their work is progressing and more importantly I get forced to become focused once again after a few weeks of just not paying much attention to anything related to work.

This year our group has happily gained some additions and sadly seen some others leave in search of a better future. María Eugenia “Maru” Sandoval gave a talk on the work she did on Singlet Fission (SF) in the Fenna-Matthews-Olson (FMO) complex during a three month stay at the Basque Country University in Spain under the supervision of Dr. David Casanova. Aside her calculations regarding Förster theory and a modification to Marcus’ equation, Singlet Fission was explored by her as a possible mechanism in which the Photosynthetic complex FMO might transfer solar energy from the antennae to the reaction center; one that might explain the high efficiency of it.

SF is a fascinating phenomenon: So you get an excited state S1 for a molecule1 that has been struck with a suitable photon; this excited state can either radiate back to the ground state (S0) but if there were two degenerate and coupled triplets whose energies are similar to half the S1 energy then the excited state might decay into [TT]1, hence singlet fission. In some cases (e.g. polyacene crystals) one of these triplets might be located in an adjacent molecule, this creates a hole in a second molecule due to the same single photon! This means creating twice the current albeit at half the voltage in photovoltaic materials. Maru has explored the possibility of SF occurring in natural systems and we think we might be on to something; she will defend her masters thesis any day now and we should see a publication later on this year. After that, she is pondering a few interesting options for her PhD.

On the poster session, our lab was represented by Marycarmen Reséndiz, Gustavo Mondragón and Guillermo Caballero. Durbis Pazos just now joined our group so he didn’t have to present a poster but nevertheless showed up gladly to support his colleagues. Gustavo will work on other aspects regarding the photochemistry of the FMO complex while Marycarmen is working on calculating the electronic interactions of chemically modified nucleotides when incorporated into DNA strands. Guillermo had a poster on his calculations for another reaction mechanism that caught his eye while still working with the experimentalists. I’m pleased to say that Guillermo is close to being published and also close to leaving us in order to get a PhD in a prestigious university that shall remain unnamed.

Thank you guys for keeping up the good work and maintaining the quality of the research we do, here is to a year full of success both in and out of the lab! Any success this lab has is due to you.

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.

(Ligands: Green = Chloride; Blue = Cyanide)

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 aducts under study

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 *

J. Am. Chem. Soc., Article ASAP
DOI: 10.1021/ja503506a
Publication Date (Web): July 9, 2014

 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. 

 

Transition State Search (QST2 & QST3) and IRC with Gaussian09


Theoretical evaluation of a reaction mechanism is all about finding the right transition states (TS) but there are no guarantees within the available methods to actually find the one we need. Chemical intuition in the proposal of a mechanism is paramount. Let’s remember that a TS is a critical point on a Potential Energy Surface (PES) that is a minimum in every dimension but one. For a PES with more than two degrees of freedom, a hyper-surface, envisioning the location of a TS is a bit tricky, in the case of a three dimensional PES (two degrees of freedom) the saddle point constitutes the location of the TS as depicted in figure 1 by a section of a revolution hyperboloid.

400px-Saddle_point

Fig1. Saddle point on a surface (min in one direction; max in the other)

Fig 1a Pringles chips -Yuck-. They exhibit a maximum on the direction parallel to the screen and a minimum on the direction perpendicular to the screen at the same point.

Fig 1a Pringles chips -Yuck-. They exhibit a maximum on the direction parallel to the screen and a minimum on the direction perpendicular to the screen at the same point.

The following procedure considers gas phase calculations. Nevertheless, the use of the SCRF keyword activates the implicit solvent calculation of choice in order to evaluate to some degree the solvent influence on the reaction energetics at different temperatures with the use of the temperature keyword.

The first step consists of a high level optimization of all minimums involved, such as reagents, products and intermediates, with a subsequent frequency analysis that includes no imaginary eigenvalues.

In order to find the structures of the transition states we use in Gaussian the Synchronous Transit-guided Quasi-Newton method [1] through the keywords QST2 or QST3. In the former case, coordinates for the reagents and products are needed as input; for the latter keyword, coordinates for the TS structure guess is needed also.

QST2)

%chk=file.chk
%nprocshared=n
%mem=nGB

#p opt=(qst2,redundant) m062x/6-31++G(d,p) freq=noraman Temperature=373.15 SCRF=(Solvent=Water)

Title card for reagents

Q M
Cartesian Coordinates for reagents
blank line
Title card for products

Q M
Cartesian Coordinates for products
blank line

QST3)

%chk=file.chk
%nprocshared=n
%mem=nGB

#p opt=(qst3,redundant) m062x/6-31++G(d,p) freq=noraman Temperature=373.15 SCRF=(Solvent=Water)

Title Card for reagents

Q M
Cartesian Coordinates for reagents
blank line
Title card for products

Q M
Cartesian Coordinates for products
blank line–
Title card for TS
Q M
Cartesian Coordinates for TS
blank line

NOTE: It is fundamental that the numbering order is kept constant throughout the molecular specifications of all two, or three, input structures. Hence, I recommend to build a set of molecules, save their structure, and then modified the coordinates on the same file to produce the following structure, that way the number for every atom will remain the same for every step.

As I wrote above, there are no guarantees of finding the right TS so many attempts are probably needed. Once we have the optimized structures for all the species involved in our mechanistic proposal we can plot their energies very simply with MS Excel the way we’ve previously described in this blog (reblogged from eutactic.wordpress.com)

Once we’ve succeeded in finding the structure of our TS we may run an Internal Reaction Coordinate (IRC) calculation. This calculation will connect the TS structure to those of the products and the reagents. Initial constant forces are required and these are commonly retrieved from the TS calculation checkpoint file through the RCFC keyword.

%chk=QST3_2p.chk
%nprocshared=8

#p m062x/6-31++G(d,p) IRC=(Maxpoints=50,RCFC,phase=(2,1))Temperature=373.15 SCRF=(Solvent=Water) geom=allcheck

Title Card

Q M
blank line

Finally, the IRC path can be visualized with GaussView from the Results menu. A successful IRC will link both structures along a single reaction coordinate proving that both reagents and products are linked by the obtained TS.

Hat tip to Howard Diaz who has become quite skillful in calculating these mechanisms as proven by his recent poster at the XII RMFQT a couple of weeks back. And as usual thanks to everyone who reads, comments, likes, recommends, rates and shares my silly little posts.

Summer Internships


This week has been a happy one since four new additions to our staff have been made, at least for the summer, that is. Paulina, Eliana, Javier and Daniel have come to our lab from various different towns across the nation to spend six weeks working hard in small projects related to our lines of research; namely theoretical drug carriers design. This time the drug under study is known as GTP or 3-phenyl(1H-[1]benzofuro[3,2]pyrazole and calixarenes will once again act as the potential carriers.

20130626-122705.jpg

Left to Right: Daniel, Javier, Paulina and Eliana
(Summer Interns – 2013)

They all came as part of the Dolphin Research Summer Program (link in Spanish only) in which college students spend a few weeks doing research in the lab of their choosing. This is the first time I participate as a tutor and I find it a great opportunity for young students to get familiar with certain aspects of science they wont learn inside school.

So far these past three days have been quite intense with them learning how to edit and submit a Gaussian calculation in a Linux environment. I’ve already taught them about geometry optimizations, frequency analysis, (natural) population analysis and Fukui reactivity indices calculation. There is much more to learn still, of course, but so far so good. I believe the major drawback so far has been their own eagerness since they’d like to have all the data imediately! Unfortunately they’ll have to wait for their initial calculations to converge. We started this week by doing some simple analysis of all the properties described above for the Cytosine-Guanine base pair at the B97D/6-31+G(d,p) level of theory. Luckily their calculation crashed promptly, and I find that lucky because that gave me the opportunity to teach them how to relaunch a failed calculation, which, unfortunatelly will happen more often than not.

So, welcome guys! Thanks for choosing this lab for doing your internships. I hope you find our research interesting and motivating, may this be the first step into a full time research career. Also, kudos to the Dolphin Staff for helping promote science in young Mexican students. Stay tuned for a guest post from all of them once they finish their time here.

#RealTimeChem – Happy birthday DNA!


What a happy coincidence -if indeed it was- that #RealTimeChem week happened to coincide with the sixtieth anniversary of the three seminal papers published in Nature on this day back in 1953, one of which was co-authored by J. Watson and F. Crick; of course I mean the publication for the first time of the structure of deoxyribose nucleic acid, or DNA, as we now call it.

You can get the original Nature papers from 1953 here at: http://www.nature.com/nature/dna50/archive.html (costs may apply)

Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid 737

J. D. WATSON & F. H. C. CRICK
doi:10.1038/171737a0

Molecular Structure of Nucleic Acids: Molecular Structure of Deoxypentose Nucleic Acids 738
M. H. F. WILKINS, A. R. STOKES & H. R. WILSON
doi:10.1038/171738a0

Molecular Configuration in Sodium Thymonucleate 740
ROSALIND E. FRANKLIN & R. G. GOSLING
doi:10.1038/171740a0

Nature’s podcast released two episodes (called ‘pastcast’) to celebrate DNA’s structure’s birthday, one of them is an interview with Dr. Raymond Gosling who in 1953 worked under Dr. Rosalind Franklin at King’s College London in diffractometry of biological molecules. If you haven’t listened to them you can get them here at nature.com/nature/podcasts. Of course, the history around the discovery of DNA’s structure is not without controversy and it has been long argued that the work of Franklin and Gossling didn’t get all deserved credit from Watson and Crick. In their paper W&C acknowledge the contribution of the general nature of DNA from the unpublished results by Franklin’s laboratory but that is as far as they went, they didn’t even mention photo 51 which Crick saw at Wilkins laboratory, who in turn got it from Gossling at Franklin’s suggestion. Still, no one can deny that the helical structure with which we are now familiar is their work, and more importantly the discovery of the specific pairing, which according to Gossling was a stroke of genious that probably couldn’t have happened in his own group, but without Franklin’s diffraction and Gossling’s crystallization  there was little they could do. Details about the process used to crystallize DNA can be heard in the aforementioned podcast, along with an inspiring tale of hard work by Dr. Gossling. Go now and listen to it, its truly inspiring.

For me it was not the story of a helix, that I was familiar with; it was the story of the specific pairing of two hélices
– Dr. Raymond Gosling

Famous Photo 51 by Dr. Rosalind Franklin and Raymond Gosling (Source: Wikipedia)

The iconic Photo 51 by Dr. Rosalind Franklin and Raymond Gosling (Source: Wikipedia)

Above, the iconic Photo 51 taken by Franklin and Gossling (have you ever noticed how most scientists refer to Franklin just as Rosalind but no one refers to Watson as James? Gender bias has a role in this tale too) To a trained crystallographer, the helical symmetry is evident from the diffraction pattern but going from Photo 51 to the representation below was the subject of hard work too.

Modern DNA representation (Source: Wikipedia)

Modern DNA representation (Source: Wikipedia)

There are million of pages written during the last 60 years about DNA’s structure and its role in the chemistry of life; the nature of the pairing and the selectivity of base pairs through hydrogen bond interactions, an interaction found ubiquitously in nature; water itself is a liquid due to the intermolecular hydrogen-bonds, which reminds us about the delicate balance of forces in biochemistry making life a delicate matter. But I digress. Millions of pages have been written and I’m no position of adding a meaningful sentence to them; however, it is a fascinating tale that has shaped the course of mankind, just think of the Human Genome Project and all the possibilities both positive and negative! DNA and its discovery tale will continue to amaze us and inspire us, just like in 2011 it inspired the Genetech company to set a Guiness World Record with the largest human DNA helix.

Genetech SF, Cal. USA (Source worldrecordacademy.com)

Genetech SF, Cal. USA (Source worldrecordacademy.com)

Happy birthday, DNA!

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