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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!

 

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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

How to read (and perhaps even write) a scientific paper


This post was inspired by this other one, featured in WordPress’ Freshly Pressed section, on how should non-scientist read a scientific paper.  While the approach presented therein is both valid and valuable, I’d like to address the way I think a scientist should read a paper, given the fact that we need to read a lot of them at all times. Each scientist has their own reading style, not to mention their own writing style, and while my CV could indicate I don’t know how to do neither one, here I present to you my scientific-paper-reading style which I consider to be the most suitable for me.

I’d like to start by emphasizing that I dive into scientific literature in a bona fide fashion. That is not to say I’m totally naive or even gullible, but even when science is all about questioning and casting doubt onto all sorts of claims, we can’t re-develop every bit of science we need. At a certain point we must start *gasp* believing trusting other scientists’ claims. Reading in what I call bona fide is not mutually exclusive with critical reading. This sort of scientific trust is earned, to a degree, mostly by two indicators: Author’s preceding reputation at the time of publication of any given paper as well as the journal’s. Both indicators aren’t without controversy and flaw.

The way I read a paper is the following: I start with the Abstract, then follow with the Conclusions, then the Results section, sometimes I read the details of the methodology and seldom read the Introduction. Let me explain.

I read the abstract first because I read in bona fide as I hope the authors wrote the paper in bona fide. If properly written, the abstract should include all the relevant information as to what was done, why, and how but also point to the knowledge derived from it all: Their conclusions! and that is why I follow with that section. I’m interested in knowing what the authors learned and ultimately want me to learn about their study. Once again I’m reading in bona fide, so I hope they weren’t tempering their results to fit their preconceptions, that all experiments were thoroughly self-judged, validated, correlated, referenced and controlled. Recently, my sister Janet, who is a physicist working on her PhD in neuroscience, told me about some friends of hers who never (shall I say, never have I ever?) read the conclusions as to not becoming biased by the authors. To me it seems like too much work having to scrutinize every piece of data again in order to come up with my own conclusions when authors, collaborators, people on the hallway down the lab (optional), referees and editors (vide infra) have already (hopefully) done it (properly). Still I put on my scientist badge and question everything I critically read in the results section trying thus to understand how did the authors reached their conclusions and asking myself if I could come up with something entirely different. No? OK, how about something slightly different? Still no? Well, do I agree with the authors on their findings and their observed results? And so on. I like thinking that my critical reading process resembles the Self Consistent Field method which iteratively reaches the best wavefunction for a set of certain given conditions, but it never reaches the exact one.

The methodology section is a bit tricky, specially when it comes to computational chemistry. Back when I was a grad student, working in an inorganic chemistry lab, I’d only read the methodology if I had any plans of reproducing the experiment, other than that I didn’t care too much if reagents were purchased from Aldrich or Fluka or if the spectrophotometer was a Perkin Elmer one, I just expected authors to have purified their reagents prior to usage and calibrated all spectrophotometers. Now in computational chemistry I read about the methods employed, which functional and what basis set were used and why were they selected are my most frequent questions, but the level of theory is usually stated in the abstract. I also take a look at what methods were used to calculate which properties; these questions are important when we have to validate our trust in the results in front of us.

Finally, I seldom read the introduction because, if the paper is relevant to my own research, I don’t need to read why is important or interesting, I’m already sold on that premise! that is why I’m reading the paper in the first place! If both me and the author act in bona fide, we both already know what the state of the art is, so lets move on because I have a ton of other papers to read. Hence, I read the introduction only when I’m trying to immerse myself in a new field or when reading something that seems interesting but which has little to do with my area of expertise. There is another reason why I almost never read introductions and that is that, even when I try to work in bona fide, there are a lot of people out there who don’t. Twice have I received the reviews from a mysterious referee who believes it would serve the work a great deal to cite two, maybe three, other papers which he or she lists for your convenience, only to find out that they all belong to the same author in each case and that they are not quite entirely related to the manuscript.

In the title of this post I also try to address the writing of a scientific paper, although I’m not an authority on it, I think today’s key phrase is bona fide. So to young and not so young scientists out there I’d ask you to write in bona fide, please. Be concise. Be convincing. Be thorough and be critical. This is science we are doing, not stamp collecting. It shouldn’t be about getting all sorts of things out there, it is about expanding the knowledge of the human race one paper at a time. But we are humans; therefore we are flawed. More and more cases of scientific misconduct are found throughout the literature and nowadays, with the speed of blogging and tweeting, we can point at too many of them. The role of bloggers in pointing this frauds, of which I’ve written before here, is the subject of recent controversy and possibly the topic of a future post. We are all being scrutinized in our work but that shouldn’t be an excuse to make up data, tinker or temper with it, to push our own personal agendas or to gain prestige in an otherwise wild academic environment.

I for one may never publish in Science or Nature; I may never be selected for any important prize, but even the promise of achieving any of those is not worth the guilt trip of lying to an entire academic society. I try then, to always remember that science is not about getting the best answers, but about posing the right questions.

What is your own style for reading papers? Any criticism to my style? How different is the style of a grad student from that of a researcher?

As usual thanks for reading, rating and commenting!

More interns!


I’ve been neglecting this blog a lot lately! It would seem as little or nothing is going on in our lab but it’s quite the opposite, a lot of good stuff is going on and most of the excitement comes from the results obtained by a few more interns.

20130905-235321.jpg

Eduardo Cruz

20130905-235352.jpg

Alberto Olmedo

Alberto and Eduardo came just as the previous group of interns left. They’re both undergrad students in Pharmaceutical Sciences at Universidad de la Cañada in southern Mexico. My good friend, Dr. María del Carmen Hernández, referred them to me to do a stay during their summer vacations. They are taking where the previous interns (Paulina, Eliana, Javier and Daniel) left and have now obtained the interaction energies for five different host-guest aducts for 3-phenyl-1H-[1]bezofuro[3,2-x]pyrazole, a tyrosine III kinase inhibitor, currently under research for the treatment of leukemia, better known to us as GTP. As before, our molecular carriers are a wide selection of functionalized-calix[n]arenes. These calculations turned out to be rather lengthy; they were all performed at the B97D/6-31+G(d,p) level of theory in order to account for dispersion forces in pi-pi interactions between the aromatic rings in both species.

The third recent addition to our lab is Monserrat Enriquez, who is a PhD student under the supervision of my good friend Dr. Eddie López-Honorato (if you haven’t checked his blog on nuclear energy and materials for nuclear reactions containment go now and follow it; encourage him to post more often!). Monserrat will be co-advised by me. Her project lies within the scope of molecular recognition, materials recovery and bioremediation; calculations and simulations will help the experimental team to point the synthesis of sequestrating agents in the right direction, or, at the very least, to have a better understanding of the forces and interactions lying beneath the formation of such complex structures.

20130905-235410.jpg

Monserrat Enriquez

Last but not least, Luis Enrique is back with a vengeance! He is determined to finish his study on other tyrosine kinase inhibitor drugs. Luis Enrique is an undergrad Chemistry student here in Toluca at the Autonomous Mexico State University, so he will come on his spare time and work from home every now and then; who knows! maybe he’ll end up with a dissertation by the time he finishes his undergrad studies!

But I’m to be left alone pretty soon, as Alberto and Eduardo will stay for a couple of weeks more and Luis Enrique will be here on his spare time. Monserrat will leave on Friday back to Saltillo in Northern Mexico to continue working on the experimental part of her research while working on her calculations from a distance.

Thanks to them for their invaluable help in the development of our research group, for their enthusiasm and hard work. You are now a part of this lab and its doors will always welcome you back!

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.

New paper in J. Phys. Chem. C


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)

Higher laying orbitals for Hg(II) complex

Higher laying orbitals for Hg(II) complex

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.

CONACyT funding was approved!


A couple of months ago, maybe a little bit more, I got the news that the project I submitted to the National Council for Science and Technology (CONACyT) was approved! Now we only have to wait for the money to actually show up and that might take a while – a long while! Nevertheless this is always very good news and we are very excited about it because this means more money for research, specifically on the electronic molecular pathways of photosynthesis.

When I submitted the project I wrote a little post about the funding scheme which seemed, if not unfair, at least flawed, and I still believe in what I wrote. To be honest I thought it wouldn’t be funded but it turns out it was but I still think the reviewing process could be better.

There is a lot of research to do – too little time to do it.

Institute of Chemistry Library flood – UNAM


If a mind is a terrible thing to waste, then wasting a collective mind is an even more terrible thing. During the past weekend the library at the institute of chemistry suffered a flood caused by a broken pipe just above it, which incidentally happens to be the lab were I used to work as an undergrad student. When it comes to scientific journals, our institute still relies a lot on paper issues for the oldest numbers; we can order them online but it’s just easier to Xerox it at the library if you really need to read that old reference.

This morning the librarians were appalled when noticed not only the huge puddle on the floor but all the books and scientific journals that were dripping water from the shelves. The broken pipe has been fixed and the water on the floor has been mopped. It is now the books the ones that suffer the aftermath of this accident. Not only saving the information was important; wet paper is a great culture media for fungi which in turn could pose a health threat to all users. The administrative staff immediately got to work in recruiting academics and students to help the drying process: “Heal a book!“, they informally called it. Everyone grabbed an item and with the help of industrial blow dryers – the kind we use in chemistry labs to dry wet glassware – and an extraordinary amount of paper towels, each person got to dry the journals page by page.

I got an item that corresponded to the British journal New Scientist, which consisted of about fifteen issues from the year 1980. When I noticed the title in my hand I wanted to switch it. Should we save first those journals with the highest impact factor? or should we work on those that are most relevant to our own research? Should we throw away Chemical Abstracts now that the whole database is online? After all, New Scientist is a magazine which summarizes research that has already been peer reviewed and published; it is journalistic work, not peer reviewed science. But I was afraid to look pedantic so I got to work on drying it.

Kudos to the library staff on organizing in promptu “Heal a book!”

Students as well as the academic and administrative staff drying journals

Each person had their own technique. Some journals had their binding covers still in good shape so they were placed open standing on the floor in front of fans. Some placed paper towels carefully between pages and after a while they would remove them and then use the blow dryer. I thought that if I heated the edges of the paper and thus dried them, capillarity would drive the moisture in the innermost part of each page outwards. Didn’t quite work, at least not in a pragmatic time scale, so I went back to page by page.

I’m glad I did so. That way I was able to find some real pieces of history which could make any scientist nostalgic. For example: I took these photos with my iPod, and if you are by any chance reading this piece on an iPhone, you must find the following  picture about Swedish research endearing.

An ancient iPad or an edgy ‘Etch-a-Sketch‘?

Yes, online doodling games were already a thought back in 1980!

Are you subscribed to this blog? That means you got a notification by e-mail. So what? No big deal! Well, back in 1980 Britain was getting excited over a new form of comunication called the ‘Electronic Mail’ (available only at a couple of post offices). Besides, you wouldn’t have been able to get that message nor read this post on an HP Matrix Machine (you can’t even find a decent link in google about it nowadays!)

But scientists are not all about working, we like games too! So how about purchasing a ‘Hungarian Magic Cube‘ or a ‘Chess Computer‘?

An 80’s sensation!

E-chess

We also love a juicy piece of gossip. For instance, did you know that John Maddox was a controversial editor for Nature back in the 70’s who, as a student, went into chemistry because if he’d gone into physics he could’ve been drafted by the army in WWII to work on radars? Well me neither. But it seems that we should have known who he was, and now we do.

Sir John Maddox

There were many pieces of science news that nearly kept me in the library all night, if not for the fact that I had to drive 50 miles from Mexico City to my place in Toluca, but the one that captured my attention more than any other was the news of a European dream envisioned more than three decades ago; a dream from a group of scientists about looking for answers, like any other group of scientists, answers that are fundamental for the understanding of our universe and the understanding of matter, back when some of the biggest questions hadn’t even been fully posed, this group of visionaries agreed on taking the necessary steps to build an enormous subatomic-particle Supercollider for the European Center for Nuclear Research, better known as CERN.

The announcement of grand things to come

Back in 1980 I was already alive but I was only two years old. I could barely talk and had no idea what the word ‘future‘ meant, let alone what I’d become when it reached me. Now, even if I’m not a particle physicist I get excited about the news regarding the finding of the Higgs Boson and even if I’m not an astronomer I also get excited about pictures from the Curiosity Rover on Mars. I am a scientist. One out of hundreds of thousands or perhaps even millions, and this is part of my collective memory, the memory of the work of those who paved the road for us, those giants upon whose shoulders we struggle day by day to stand with dignity and against all odds. But here is the thing: those giants are actually made of dwarfs, millions of them; millions of us. Thousands and thousands of papers written, reviewed and published; papers that collectively gather the scientific experience summed up in rigorous experiments both successful and failed.

Preserving the information in those wet journals is important despite the fact you can get them all online. I hope one day a bored chemistry grad student goes to the library and browses old issues of New Scientist and other journals just for fun; they’ll go for a trip down a collective Memory Lane which will remind them that if they can dream it in the present, they can make it come true in the future.

100,000 visitors!


This morning at around 9 AM, I guess, this little blog of mine reached a significant milestone: It reached 100,000 visitors!

The blog started about 3.5 years ago when I was still living in Romania working at the lab of the late Prof. Dr. Ioan Silaghi-Dumitrescu. Back then I started the blog as a way to make my research visible to others and maybe in that way I could gain some notoriety which could help me in the near future to land a fine research position. None of that happened. I remember we were having some issues with some PCM calculations in the lab and after a lot of hard work and a lot of asking we gather some tips to work with implicit solvation models in Gaussian. Prof. Silaghi suggested we should write them down and put them on the wall of the lab so we had them available at all times; it was then when I suggested we could place them in my little blog so we had them available online. This happened in September 2009, three years ago, and little did I know, this post became quite popular, it is still one of the most visited ones in the blog. Later on we had a similar problem while trying to visualize Natural Bond Orbitals, there was too much information but it was all scattered, so we did it again, we gathered some of the info and made a new post which became also quite popular.

100,012 visitors this morning. Thanks!

Little have I written about my own work, mostly because of fear of being scooped, I guess.

I’d like to thank every reader who has ever liked, commented, rated, favorited, shared, reblogged, blogrolled, recommended any of my posts and the nearly 200 people who have subscribed or followed this little blog, as I like to call it.

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