Scientists using sophisticated computational chemistry techniques have identified a new pathway for how sulfur particles can form in the atmosphere of Venus. These results may help to understand the long sought-after identity of the mysterious ultraviolet absorber on Venus. 

“We know that the atmosphere of Venus has abundant SO₂ and sulfuric acid particles. We expect that ultraviolet destruction of SO₂ produces sulfur particles. They are built up from atomic S (sulfur) to S₂, then S_4, and finally S₈. But how is this process initiated, that is, how does S₂ form?” said Planetary Science Institute Senior Scientist James Lyons. 

One possibility is to form S₂ from two sulfur atoms, that is, a reaction of S and S. Molecules of S₂ and S₂ can then combine to form S₄, and so on. Sulfur particles can form either by condensation of S₈ or by condensation of S₂, S_4, and other allotropes – different physical forms in which an element can exist – which then rearrange to form condensed S₈. 

“Sulfur particles, and the yellow sulfur we more commonly encounter, is made up of mostly S₈, which has a ring structure. The ring structure makes S₈ more stable against destruction by UV light than the other allotropes. To form S₈, we can either start with two S atoms and make S₂, or we can produce S₂ by another pathway, which is what we’ve done in the paper,” said Lyons. 

“We found a new pathway for S₂ formation, the reaction of sulfur monoxide (SO) and disulfur monoxide (S₂O), which is much faster than combining two S atoms to make S₂,” Lyons said. 

“For the first time, we are using computational chemistry techniques to determine which reactions are most important, rather than waiting for laboratory measurements to be done or using highly inaccurate estimates of the rate of unstudied reactions. This is a new and very much needed approach for studying the atmosphere of Venus,” Lyons said. “People are reluctant to go in the lab to measure rate constants for molecules made up of S, chlorine (Cl), and oxygen (O) – these are difficult and sometimes dangerous compounds to work with. Computational methods are the best – and only – alternative. 

Computational methods were used to supercompute the rate constants and to determine the expected reaction products. These are state-of-the-art computational models (what we call ab initio models). These ab initio calculations were done by the authors from Spain and the University of Pennsylvania. 

“This research illustrates another pathway to S₂ and sulfur particle formation. Sulfur chemistry is dominant in Venus' atmosphere, and very likely plays a key role in the formation of the enigmatic UV absorber. More generally, this work opens the doors to using molecular ab initio techniques to disentangle the complex chemistry of Venus,” Lyons said. 

Antonio Francés-Monerris of Departament de Química Física, Universitat de València, Spain is lead author on the paper. Coauthors include Javier Carmona-García and Daniel Roca-Sanjuán also of the Universitat de València, Alfonso Saiz-Lopez of the Institute of Physical Chemistry Rocasolano in Madrid, and Tarek Trabelsi and Joseph S. Francisco of the University of Pennsylvania.

The approach improves avoidance of ‘bystander’ edits in CRISPR-base editor treatments

Want to keep the riffraff out of the gene pool party? Sneak in and slam the gate before they arrive. 

That’s the central idea of a new strategy by Rice University scientists who seek to avoid gene-editing errors by fine-tuning specific CRISPR-base editing strategies in advance.

Rice chemical and biomolecular engineer Xue Sherry Gao and chemist Anatoly Kolomeisky and their labs' combined theory and experimentation for a comprehensive approach to building better base editors, molecular machines that target and fix faulty DNA at single-base resolution. 

The study describes the molecular processes that base editors use to manipulate strands of DNA, cutting them where necessary and making way for replacement code. When it works, as it increasingly does to treat genetic diseases like sickle cell anemia and some cancers, the editor only edits the intended nucleotide. 

And when it doesn’t, that’s because bystander edits can cause undesired effects. 

The Rice strategy primarily seeks to eliminate wayward edits to bystanders, nucleotides adjacent to the base editor’s target. Gao’s lab previously introduced tools to improve the accuracy of CRISPR-based edits of cytosine mutations up to 6,000-fold.

For the new project, she engaged the Kolomeisky lab to help create a theoretical framework to eliminate trial and error in the design of a library of editors. These would better target mutations that cause disease while avoiding bystanders. In the process, the framework could help scientists better understand the chemical and physical processes that take place during base editing.

“Sherry and other experimental scientists already had results that worked,” Kolomeisky said, referring to the earlier paper, in which the lab used its editor to convert cytosines to thymines, correcting the DNA mutations while avoiding otherwise vulnerable cytosines upstream. “But despite these amazing developments, there’s been no microscopic understanding of what we have to do with these protein systems to improve editing.”

He said Qian Wang, a former postdoctoral researcher in Kolomeisky’s lab and now an assistant professor at the University of Science and Technology of China (USTC), Hefei, took on the challenge, using Gao’s cytosine experiment as a baseline. 

“We applied the model for that result and got some important parameters we then used to design what mutations and where are needed to get precise editing,” Kolomeisky said. “Ultimately, this symbiosis of theory and experiment allows us to work in a smart way.”

Their strategy combines molecular dynamics simulations and stochastic (aka random) models that pinpoint the binding energies between molecules required to achieve maximum editing selectivity. Experiments in Gao’s lab validated the results. 

Critically, the framework includes a way to characterize the binding affinity between deaminases -- enzymes that catalyze the removal of an amino group from a molecule -- and single-stranded DNA (ssDNA).

Ideally, they said, the deaminase stays on the ssDNA just long enough to complete the primary edit and releases before inadvertently editing a bystander site. 

“The important thing here is that one mutation doesn't work for different systems,” Kolomeisky said. “So, for every system, you have to do this procedure again, but at least it's clear what should be done.”

“The model has been very successful in reflecting what has already been done experimentally,” Gao said. “But since then, we’ve been able to turn down bystander effects in other base-editing systems. 

“Because the number of mutants could be in the thousands, it’s unrealistic for experimentalists alone to verify individual base editors,” she said. “Only this multidisciplinary approach will allow us to build a huge library of editors computationally, then narrow the numbers down to the most promising candidates for further experimental verifications. That’s what we’re working toward.”