Computational Chemistry: 2014 in numbers

In 2014 we learnt that two of the germinal DFT papers (by Becke and Lee, Yang and Parr) are amongst the top ten most cited scientific papers of all time, and of chemistry papers published in the last ten years, the fourth and fifth most cited again relate to computational research (Truhlar and Hess, respectively). In this vein I thought it would be interesting to perform a (pseudo)-scientific analysis of the usage of computation in chemistry research in, and in the years leading up to, 2014 as judged by bibliometric data.

Searching all 2014 chemistry papers in the Web of Science for mention of "computation" or "computational" in either the article title, abstract or keywords suggests that approximately 2.7% of chemistry research involved computation of some variety this year (9,101 of a staggering 331,699 papers). This is most likely an underestimate since searching for more specific phrases such as "DFT" will turn up more hits. The same analysis over previous years reveals a steady increase in the proportion of chemistry research using computation from 0.6% in 1994, to 1.1% in 2004 and 2.2% in 2010.

Around 20% of all the computational chemistry papers published in 2014 emanate from the USA, more than double the closest competitor, China. The top ten nations in terms of publications are USA 19.5%, China 9.3%, Germany 6.1%, India 4.3%, France 4.0%, Italy 3.8%, Spain 3.7%, England 3.6%, Japan 2.7% and Canada 2.4% - making nearly 60% of the total output. A decade ago in 2004 the ten most prolific countries accounted for around 87% of total output, which indicates that recent years have witnessed a greater global involvement  in computational chemistry. Noticeable trends are seen in individual nations share of the computational chemistry pie, with the USA and some European nations effectively halving their fraction of papers between 2004 and 2014, with China's output nearly doubling from 5.4% in 2004 to 9.3% in 2014 and the emergence of India from outside the top ten into fourth place in 2014. It should be borne in mind that the globalization of science will inevitably lead to some over counting of papers here, due to multiple addresses appearing on the same paper.

Post Transition State Dynamics in Enzyme Catalysis

Dynamics simulations performed on the DFT potential energy surface reveal the role of post-transition state dynamics in natural product biosynthesis, and point towards another role for enzymatic control over product selectivity.

Multiple cyclization and rearrangement steps are involved in the biosynthesis of terpenoid natural products, each providing the possibility for the generation of a number of isomeric products, and so it is necessary for enzymatic control over which product is eventually formed. While selectivity in kinetically-controlled reactions is well known to result from differences in the relative (free) energies of the competing transition states, there appear to be a growing number of reactions in which reactions isomeric products (and hence selectivity) may also arise following a single transition state, due to a bifuration of the reaction pathway into two downhill pathways toward products. In fact, in a recent Chemistry and Engineering News piece on reaction path bifurcations in organic and bioorganic chemistry, Dan Singleton has estimated the proportion of such reactions to be around 20%, much higher than previously imagined.

Idealized potential energy surface featuring a bifurcation after the saddle point; the point at which the pathway splits into two is a valley ridge inflection (VRI).

In their recent article in Nature Chemistry Hong and Tantillo use quasiclassical dynamics calculations to interrogate the enzymatic biosynthesis of militradiene, applying Newtonian equations of motion with the forces that result from the (Born-Oppenheimer) potential energy surface obtained from density functional theory (B3LYP/6-31+G(d,p)) calculations on-the-fly. These calculations utilise energy/ gradient evaluations with standard quantum chemistry software, propagating the trajectory with Singeton's Progdyn code.  In this study hundreds of trajectory calculations were performed, each initiated in the region of the rate-limiting transition structure (i.e. the dynamical bottleneck). This is necessary since quantum chemical calculations reveal the underlying potential energy surface to be remarkably complex, with multiple, sequential bifurcations along the reaction path all occurring after an initial rate-limiting transition state. This initial TS is connected to several isomeric intermediates via steepest-descent pathways on the potential energy surface without any intervening minima, such that the redistribution of intramolecular vibrational energy is not significantly faster than the passage towards product(s) - the  assumptions underlying classical transition state theory are clearly inadequate for such a reaction mechanism.

Even though there a large number of stationary points on the underlying energy surface, each of which corresponds to isomeric carbocationic intermediates, the dynamics simulations reveal that only two constitutionally distinct carbocation structures are formed in appreciable amounts. While one of these structures corresponds to the natural product’s direct precursor, the other possesses a diterpene skeleton previously unknown in nature. Thus, to ensure selective formation of miltiradiene it appears that the enzyme must exert control over the dynamical preferences of the substrate in traversing the underlying potential energy surface once it has passed through the transition state. Due to the computational demands the simulations have yet to be performed in the presence of the enzyme active site, so we must wait further exploration of the specific interactions which influence the dynamics of this reaction. However, we can expect that the electrostatic environment of the active site, which include the dissociated pyrophosphate counterion, will play an important role in dynamical steering towards the natural product as has been shown for bornyl diphosphate synthase

Chemical Networks (Triple Header!)

1. Rewiring Chemistry: Algorithmic Discovery and Experimental Validation of One-Pot Reactions in the Network of Organic Chemistry 
2. Parallel Optimization of Synthetic Pathways within the Network of Organic Chemistry Chemical
3. Network Algorithms for the Risk Assessment and Management of Chemical Threats 

A back-to-back-to-back (!) set of three papers in Angewandte Chemie from Bartosz Grzybowski and co-workers. All three articles concern the development of Chemical Networks and their application in synthetic chemistry, of which more later. It is often said that the realm of synthesis is both art and science, however, the wealth of empirical observations made over centuries of making molecules underpin the field. As Grzybowski remarks here, “it is simply beyond cognition of any individual human to understand and analyze all this collective chemical knowledge”, and most chemists already search online synthesis databases to perform individual steps, but perhaps the role of automated computational synthetic route selection, and reaction design is set to grow? Also see Dean Tantillo's recent post on CCH.

Grzybowksi’s group has constructed a network of organic chemistry (NOC) from reactions in the chemical literature since 1779 until present day: reactants and products are represented by nodes in this graph and known chemical interconversions by edges. From this NOC containing seven million reactions, the first paper of the series seeks to discover new ways of performing consecutive reactions in the same vessel (so-called “one pot” reactions). From known reactions that interconvert A to B and B to C, the authors have coded filters that check for compatability between solvents, reagents, catalysts etc so that the two steps may be performed in the same reaction vessel, thus creating a novel way to prepare C from A in one step. Typically synthetic organic protocols are the result of much tinkering and optimization studies in the lab: in contrast the NOC predictions have yield a number of two, three and four step one-pot reactions that give moderate to good yields without any human optimization.

In the second paper the group turn their attention to designing “optimal” reaction pathways to synthesise a given target molecule. Again the NOC is used, this time to propagate backwards from the target via an initial synthetic plan to starting materials. A Metropolis Monte Carlo algorithm is used to randomly sample alternative routes in order to minimize a penalty function associated with the cost of performing each step. Impressively this approach has been used already by a synthesis company to reduce their costs. Additional costs such as waste disposal or energy costs associated with heating/cooling are undoubtedly important for chemistry on the process scale, and perhaps these could be incorporated in future implementations of the optimization.

The third application of a chemical network considers the synthesis of chemical warfare agents. Reaction networks are explored starting from commonly available household chemicals. Thankfully the paper is careful not to disclose any of the synthetic steps involved, and the authors propose strengthening existing regulation of substances by not only regulating single molecules but also combinations of reagents that have been ranked according to game theory as more likely to be used. 

Hydrogen-bond stabilization in oxyanion holes: grand jeté to three dimensions

Luis Simón and Jonathan M. Goodman, Organic and Biomolecular Chemistry, 2012, 10, 1905

Simón (University of Salamanca) and Goodman (University of Cambridge) have in recent years focussed on hydrogen-bonding catalysts in synthetic organic chemistry, examining the origins of rate enhancement and stereoinduction (e.g. J Am Chem Soc 2009, 131, 4070-4077). The use of low molecular weight hydrogen-bonding catalysts derived from organic rather than transition-metal based compounds, or "organocatalysis", has grown rapidly and considerably in recent years, in particular using chiral amines and phosphoric acids, along with mechanistic and predictive computational studies.

Simón and Goodman now direct their attention to hydrogen bonding motifs found in enzymatic catalysis.  Their recent article in RSC journal OBC reveals a rather unexpected geometric preference for nature's hydrogen bonds, that seems to contradict much of the dogma surrounding enzymatic catalysis: namely that transition states in so-called "oxyanion holes" are not optimally stabilised, rather, it is the activation barrier relative to the bound substrate that is minimised instead.

The computational approach employed by the authors is multi-faceted: data-mining is used to compare crystallographic hydrogen-bonding motifs found in PDB and CSD structures, cluster models of enzyme active sites are computed with DFT (often termed "theozyme" calculations, an approach advanced by Himo and Houk), QM:MM calculations are performed to locate a transition state for a rather larger active site model, and classical MD simulations are performed on an oxyanion hole containing enzyme.

A comparison of small molecule (CSD) and protein (PDB) crystal structures reveals different empirical distributions for the dihedral angle between a bound carbonyl group and two H-bond donors. Whilst CSD structures reveal a preference for planar coordination, the two polar hydrogen atoms lying more-or-less where students of organic chemistry are tought to envisage the sp2 "rabbit ear" lone pairs, the PDB structures tell a different story: the H-bond donors are more likely to be found in a plane perpendicular to the carbonyl. MD simulations reveal that this angular distribution is well maintained and not easily distorted even with the application of large constraining forces, so any kind of induced fit is extremely unlikely to alter the hydrogen-bonding geometry.

The key effect of having two hydrogen bond donors perpendicular to the plane of a carbonyl group is suboptimal substrate binding, which results in an overall reduction of the activation barrier to achieve the oxyanion transition state (presumably due a greater electrostatic component to binding, the oxyanion transition state is less fussy about coordination geometry). The contrast between a traditional depiction of carbonyl in-plane H-bonds (here represented by Da Vinci's Vitruvian man) and the authors' current model, which is likened to a ballerina's grand jeté, that gives this paper its title. On the basis of activation barriers computed with DFT, the authors estimate this effect to have an impact of around 2 kcal/mol in barrier lowering, which while only a small fraction of the overall barrier height, is comparable in importance with other contributions to catalysis such as tunnelling.