Dealing with Spin Contamination
Most organic chemistry deals with closed shell calculations, but every once in a while you want to calculate carbenes, free radicals or radical transition states coming from a homolytic bond break, which means your structure is now open shell.
Closed shell systems are characterized by having doubly occupied molecular orbitals, that is to say the calculation is ‘restricted’: Two electrons with opposite spin occupy the same orbital. In open shell systems, unrestricted calculations have a complete set of orbitals for the electrons with alpha spin and another set for those with beta spin. Spin contamination arises from the fact that wavefunctions obtained from unrestricted calculations are no longer eigenfunctions of the total spin operator <S^2>. In other words, one obtains an artificial mixture of spin states; up until now we’re dealing only with single reference methods. With each step of the SCF procedure the value of <S^2> is calculated and compared to s(s+1) where s is half the number of unpaired electrons (0.75 for a radical and 2.0 for triplets, and so on); if a large deviation between these two numbers is found, the then calculation stops.
Gaussian includes an annihilation step during SCF to reduce the amount of spin contamination but it’s not 100% reliable. Spin contaminated wavefunctions aren’t reliable and lead to errors in geometries, energies and population analyses.
One solution to overcome spin contamination is using Restricted Open Shell calculations (ROHF, ROMP2, etc.) for which singly occupied orbitals is used for the unpaired electrons and doubly occupied ones for the rest. These calculations are far more expensive than the unrestricted ones and energies for the unpaired electrons (the interesting ones) are unreliable, specially spin polarization is lost since dynamical correlation is hardly accounted for. The IOP(5/14=2) in Gaussian uses the annihilated wavefunction for the population analysis if acceptable but since Mulliken’s method is not reliable either I don’t advice it anyway.
The case of DFT is different since rho.alpha and rho.beta can be separated (similarly to the case of unrestricted ab initio calculations), but the fact that both densities are built of Kohn-Sham orbitals and not true canonical orbitals, compensates the contamination somehow. That is not to say that it never shows up in DFT calculations but it is usually less severe, of course for the case of hybrid functional the more HF exchange is included the more important spin contamination may become.
So, in short, for spin contaminated wavefunctions you want to change from restricted to unrestricted and if that doesn’t work then move to Restricted Open Shell; if using DFT you can use the same scheme and also try changing from hybrid to pure orbitals at the cost of CPU time. There is a last option which is using spin projection methods but I’ll discuss that in a following post.
Stability of Unnatural DNA – @PCCP #CompChem
As is the case of proteins, the functioning of DNA is highly dependent on its 3D structure and not just only on its sequence but the difference is that protein tertiary structure has an enormous variety whereas DNA is (almost) always a double helix with little variations. The canonical base pairs AT, CG stabilize the famous double helix but the same cannot be guaranteed when non-canonical -unnatural- base pairs (UBPs) are introduced.
Figure 1
When I first took a look at Romesberg’s UBPS, d5SICS and dNaM (throughout the study referred to as X and Y see Fig.1) it was evident that they could not form hydrogen bonds, in the end they’re substituted naphtalenes with no discernible ways of creating a synton like their natural counterparts. That’s when I called Dr. Rodrigo Galindo at Utah University who is one of the developers of the AMBER code and who is very knowledgeable on matters of DNA structure and dynamics; he immediately got on board and soon enough we were launching molecular dynamics simulations and quantum mechanical calculations. That was more than two years ago.
Our latest paper in Phys.Chem.Chem.Phys. deals with the dynamical and structural stability of a DNA strand in which Romesberg’s UBPs are introduced sequentially one pair at a time into Dickerson’s dodecamer (a palindromic sequence) from the Protein Data Bank. Therein d5SICS-dNaM pair were inserted right in the middle forming a trisdecamer; as expected, +10 microseconds molecular dynamics simulations exhibited the same stability as the control dodecamer (Fig.2 left). We didn’t need to go far enough into the substitutions to get the double helix to go awry within a couple of microseconds: Three non-consecutive inclusions of UBPs were enough to get a less regular structure (Fig. 2 right); with five, a globular structure was obtained for which is not possible to get a proper average of the most populated structures.
X and Y don’t form hydrogen bonds so the pairing is pretty much forced by the scaffold of the rest of the DNA’s double helix. There are some controversies as to how X and Y fit together, whether they overlap or just wedge between each other and according to our results, the pairing suggests that a C1-C1′ distance of 11 Å is most stable consistent with the wedging conformation. Still much work is needed to understand the pairing between X and Y and even more so to get a pair of useful UBPs. More papers on this topic in the near future.
I’m putting a new blog out there
As if I didn’t have enough things to do I’m launching a new blog inspired by the #365papers hashtag on Twitter and the naturalproductman.wordpress.com blog. In it I’ll hopefully list, write a femto-review of all the papers I read. This new effort is even more daunting than the actual reading of the huge digital pile of papers I have in my Mendeley To-Be-Read folder, the fattest of them all. The papers therein wont be a comprehensive review of Comp.Chem. must-read papers but rather papers relevant to our lab’s research or curiosity.
Maybe I’ll include some papers brought to my attention by the group and they could do the review. The whole endeavor might flop in a few weeks but I want to give it a shot; we’ll see how it mutates and if it survives or not. So far I haven’t managed to review all papers read but maybe this post will prompt to do so if only to save some face. The domain of the new blog is compchemdigest.wordpress.com but I think it should have included the word MY at the beginning so as to convey the idea that it is only my own biased reading list. Anyway, if you’re interested share it and subscribe, those post will not be publicized.
Unnatural DNA and Synthetic Biology
Ever since I read the highly praised article by Floyd Romesberg in Nature back in 2013 I got really interested in synthetic biology. In said article, an unnatural base pair (UBP) was not only inserted into a DNA double strand in vivo but the organism was even able to reproduce the UBPs present in subsequent generations.
Romesberg’s Nucleosides. No Hydrogen bonding is formed between them!
Inserting new unnatural base pairs in DNA works a lot like editing a computer’s code. Inserting a couple UBPs in vitro is like inserting a comment; it wont make a difference but its still there. If the DNA sequence containing the UBPs can be amplified by molecular biology techniques such as PCR it means that a polymerase enzyme is able to recognize it and place it in site, this is equivalent to inserting a ‘hello world’ section into a working code; it will compile but it’s pretty much useless. Inserting these UBPs in vivo means that the organism is able to thrive despite the large deformation in a short section of its genetic code, but having it replicated by the chemical machinery of the nucleus is an amazing feat that only a few molecules could allow.
The ultimate goal of synthetic biology would be to find a UBP which codes effectively and purposefully during translation of DNA.This last feat would be equivalent to inserting a working subroutine in a program with a specific purpose. But not only could the use of UBPs serve for the purposes of expanding the genetic code from a quaternary (base four) to a senary (base six) system: the field of DNA origami could also benefit from having an expansion in the chemical and structural possibilities of the famous double helix; marking and editing a sequence would also become easier by having distinctive sections with nucleotides other than A, T, C and G.
It is precisely in the concept of double helix that our research takes place since the available biochemical machinery for translation and replication can only work on a double helix, else, the repair mechanisms get activated or the DNA will just stop serving its purpose (i.e. the code wont compile).
My good friend, Dr. Rodrigo Galindo and I have worked on the simulation of Romesberg’s UBPs in order to understand the underlying structural, dynamical and electronic causes that made them so successful and to possibly design more efficient UBPs based on a set of general principles. A first paper has been accepted for publication in Phys.Chem.Chem.Phys. and we’re very excited for it; more on that in a future post.
Grimme’s Dispersion DFT-D3 in Gaussian #CompChem
I was just asked if it is possible to perform DFT-D3 calculations in Gaussian and my first answer was to use the following keyword:
EmpiricalDispersion=GD3
which is available in G16 and G09 only in revision D, apparently.
There are also some overlays that can be used to invoke the use dispersion in various scenarios:
IOp(3/74=x) Exchange and Correlation Potentials
| -77
-76 -60 -59 |
DSD-PBEP86 (double hybrid, DFT-D3).
PW6B95-D3. B2PLYP-D3 (double hybrid, DFT-D3). B97-D (DFT-D3). |
IOp(3/76=x) Mixing of HF and DFT.
| -33 | PW6B95 and PW6B95-D3 coefficients. |
IOp(3/124=x) Empirical dispersion term.
| 30
40 50 |
Force dispersion type 3 (Grimme DFT-D3).
Force dispersion type 4 (Grimme DFT-D3(BJ)). Force dispersion type 5 (Grimme D3, PM7 version). |
The D3 correction method of Grimme defines the van der Waals energy like:
 |
where coefficients 
are adjusted depending on the geometry of atoms i and j. The damping D3 function for is:
 |
where the values of s are adjustable parameters fit for the exchange-correlation functionals used in each calculation.
Is #OpenAccess a first world problem?
The goal of any scientist is to generate new knowledge and then it would be a fair assumption that most scientists are inclined to share that knowledge with as many people as possible in a noble effort to improve the world in which we live; in fact, that is the very -underlying- reason why we publish articles of all our research, so every bit of knowledge generated in our labs goes not only on record but is available for testing and questioning. The Open Access (OA) supporters rightfully wish that all publications were accessible to anyone interested without having a middleman such as a big publisher controlling access and making a profit along the way.
A while ago there was a rather noble initiative in Mexico to have all publicly funded research fully available to everybody; sounds reasonable but here is the catch: Our research would have to be published in a public online platform created, managed and operated by the state with public money. This means the Mexican tax payers would have to pay not only for research to be done but to be stored and curated also. On top of that, this platform would require to become somehow visible to other researchers in other countries in order for it not only to gather attention and recognition from the larger scientific community but also to get their proper scrutiny; and that might not a be task that the state is good at doing. Furthermore, once our research is made public through this platform we might have a copyright problem when submitting it to a mainstream traditional journal with a quantifiable IF and whether we like it or not – whether we believe in it or not – IF is a quick go-to measure with which researchers are qualified by current and future employers, in fact, permanence in certain institutions as well as organizations rely on the continuous publishing of peer reviewed indexed articles.
When I started doing research here at IQ-UNAM dollars were about eleven pesos each, they are now over twenty yet my budget is still pretty much the same and is always in pesos, not dollars, so a larger gap keeps building up. So to me, paying for an OA is becoming more and more expensive everyday and although there are very prestigious, legitimate, peer reviewed, indexed OA journals the publication fee is an important factor to consider. If I indeed have the money available I may better think twice about saving it by going to a traditional journal and use it for other purposes. And in the end, fair or not, does everybody really want to read about my calculations? I really doubt so. My personal take is to publish in a traditional journal* and then blog about it in a more relaxed way here, plus making it visible in several platforms such as Mendeley, Academia.edu or ResearchGate and share it with others whenever possible.
It would be fairly easy to assume from the title and previous line that I oppose Open Access publications but then again that would be a wrong assumption. The broader answer is that I am for OA but that I don’t think the current scientific landscape makes it a terrific idea. First, employers would have to stop fixating in IFs and prestigious titles and then there would have to be enough money for paying OA’s or making the decision between paying the fee or using the money for other things; and that right there is what makes it a First World problem to me.
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:
Comp. Chem. problems: no line for women’s restroom but men’s is out the door. 😦 #drugalchemy pic.twitter.com/BFlxXvd7H6
— David Mobley (@davidlmobley) May 17, 2016
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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Annual state of the Research Group
Like everybody else, we are doing a brief recount of the achievements of this lab during 2016 if for no better reason because it helps me map my annual report.
We published seven articles:
- A Mixed DFT-MD Methodology for the In Silico Development of Drug Releasing Macrocycles. Calix and Thia-Calix[n]Arenes as Carriers for Bosutinib and Sorafenib Journal of Computational Chemistry 2016, 37, 10, 940–946
- In silico design of calixarene-based arsenic acid removal agents J Incl Phenom Macrocycl Chem (2016) 85:169–174
- Aromatization of pyridinylidenes into pyridines is inhibited by exocyclic delocalization. A theoretical mechanistic assessment Tetrahedron 72 (2016) 4194-4200
- Reactivity of electrophilic chlorine atoms due to σ-holes: a mechanistic assessment of the chemical reduction of a trichloromethyl group by sulfur nucleophiles Phys. Chem. Chem. Phys., 2016, 18, 27300-27307
- Ab Initio Modeling Of Friction Reducing Agents Shows Quantum Mechanical Interactions Can Have Macroscopic Manifestation J. Phys. Chem. A, 2016, 120 (46), pp 9244–9248
- Crystal Structure and DFT Studies of 4-Methyl-N-(1-phenylethyl)-N´-(1-phenylethylidene)benzenesulfonohydrazide. Evidence of a carbene insertion in the formation of acetophenone azine fromacetophenone p-toluensulfonyl hydrazone. Canadian Journal of Chemistry 2016 (doi: 10.1139/cjc-2016-0183)
- Synthesis and Crystal Structures of Stable 4-Aryl-2-(trichloromethyl)-1,3-diaza-1,3-butadienes Synthesis 2016, 48, 2205–2212
Two students got their degrees:
- María Eugenia “Maru” Sandoval got her Masters Degree with a thesis on mechanisms for the excitonic transference in photosynthetic pigments.
- Gustavo “Gus” Mondragón got his Bachelor of Sciences Degree also with a thesis on mechanisms for the excitonic transference in photosynthetic pigments.
And even a patent was filed! (more on that next year when appropriate.)
We participated in the annual Mexican Meeting on Theoretical Physical Chemistry with four posters and the internal symposium both at CCIQS and the Institute of Chemistry.
2016 was a great year for us and we hope to have an even better 2017 but just as before it will only be possible thanks to the hard work and dedication of all the members of this lab, -some of which have now left us to pursuit higher ends like Maru Sandoval who leaves for Spain and Guillermo Caballero who is already at Cambridge- and also to my colleagues who keep inviting us to collaborate in exciting projects. We have new members in the lab and also new research interests but the one common denominator throughout the years in the lab is fun; having fun in doing chemistry always.
Thank you to everyone who has ever read this blog and to those who have dropped a line here and there; I know I’ve neglected this space during this year, I want to fix it in 2017. May next year be awesome for everyone; lets make it so!
Finite Element(s) Chemistry
(Ah! Mathematicians, did you see what I did there?)
There are a number of appalling videos on line in which iPhones are destroyed by various means. From a chemist standpoint, the reason why I’m so disgusted with them is the waste of rare elements which go into the making of their components: From Neodymium to Indium, most of these metals come from conflict zones in which they are extracted in the most precarious conditions imaginable, but furthermore, they are so scarce the production of electronics is almost unsustainable. I wont post any links to these infuriating videos so as to not direct traffic to any of them, instead I will direct your attention to a wonderful book titled The Elements of Power: Gadgets, Guns, and the Struggle for a Sustainable Future in the Rare Metal Age by David S. Abraham. (Sheesh! Nobody uses short titles anymore? Can you imagine Nabokov writing Lolita: A little girl with a not so little mind and the professor who picked up on that? I digress.) It is hard not to read this long-titled book and feel a tad guilty; it is in fact a bit blackmailing but above all, realizing what a wasteful society (ugh! I hate that word) we are makes a strong wake up call to the future of sustainability. I would never claim that the solution is renouncing to technology but instead to find a sustainable technology within the framework of current technology. Easier said than done -of course- but stopping waste of such precious resources should be the first step in everyones mind, and don’t even get me started on balloons filled with He! In all fairness, one can also find a lot of scary articles on line from dubious to respectful on how smartphones and other rare-metals-containing gadgets are damaging the Earth.
Last year I enjoyed reading Andy Weir’s novel The Martian (later a major motion picture from Alien’s director Ridley Scott), in which an astronaut is stranded in Mars -left for dead by his crewmates, with nothing but the finite supplies of the station and his knowledge of chemistry, botany and engineering, all of which allows him to survive by extending, but above all reusing, those resources which included not only food but O2, H2O and even hydrazine, H2N2 originally intended for fuel but from where he now gets H2 for synthesizing a larger supply of water by reacting it with the O2 pulled out of the CO2-filled Martian atmosphere. I’m pretty sure Weir didn’t intend this novel to be a metaphor but it definitely works well as one of the limited resources available on Earth and the necessity of optimizing their use, collecting and disposal. Resources on Earth seem infinite, or they at least they did back when the industrial revolution started.
I guess the point is that sustainability goes hand in hand with using the least resources to get new ones as well as with avoiding their waste. I think one must agree that Chemistry, like no other science, has shaped our world for better and worse.
I haven’t rambled on sustainability in a while. Feels bad. Must be the winter.
Mexican Phys.Chem. Meeting XVth edition
For the fifth year in a row my research group has participated in this traditional meeting on theoretical and computational chemistry, now at the beautiful city of Merida in southeastern Mexico.
Several distinguished international guests included Profs. Jose Luis Mendoza (Florida State University), Adrián Roitberg (University of Florida), Vincent Ortiz (Auburn University) and Paul Ayers (McMaster U. Canada); Their contributions rounded up nicely those of household names like Drs. Alberto Vela, Gabriel Merino (CINVESTAV) (the latter was also the main organizer), Jesus Hernández-Trujillo (UNAM), Jose Luis Gazquez (UAM-I), Óscar Jimenez (Guanajuato), and so many others who were also present.
My students presented four posters summarized below:
1) Maru Sandoval and Gustavo Mondragón on Photosynthesis, particularly the search for exciton transference mechanisms in both natural and theoretical arrangements of photosynthetic pigments. Some very exciting results have been observed; their publication is really near.
2) Raúl Torres and Gustavo Mondragón presented their work on arsenic removing calixarenes, published earlier this year, and the extension of said work to As(III) acids. Graphene oxide is now considered in our simulations as per the experimental work of our colleagues, Prof. Reyes Sierra and Prof. Eddie Lopez-Honorato.
3) Marco Diaz, Guillermo Caballero, Gustavo Mondragón and Raúl Torres had this poster on the calculation of sigma holes as descriptors for predicting pka values in organic acids. Their +1600 calculations project has found the best levels of theory (and ruled out some like B3LYP, of course) with some nice correlations. Yet, much work is still to be done but we’re on the right track.
4) Durbis Castillo presented his work on molecular docking and dynamics of a large library of HIV-1 entry inhibitors for which he uses the suite MAESTRO as a continuation of another project of ours. His enormous library is now in the hundredths of thousands and although we’re facing some technical difficulties, Durbis is thriving in his search. This is our first serious attempt towards a more mature drug discovery project; a manuscript should be ready in the first part of next year.
This guys and the rest of the lab who weren’t present are the ones who make our research flourish and they’ve all earned a day or two at the beach!
Here’s to fifteen more years of RMFQT!
