Holy Crap, Did We Just Discover a New Type of Chemical Bond?

Anion-pi interactions… right. The story starts with my scientific gig at the Free University of Berlin coming to an end. I had been roaming Europe for research, but Berlin had stolen my heart, and I was determined to find a way to stick around. So, like any loony scientist worth their salt, I locked myself in a room and started brainstorming a new research concept. When I shared it with my colleagues, they all had the same response: “Too big, too bold, it’ll never work.”

I anyway decided to take a shot in the dark and submit a proposal for a prestigious grant. And boom! The Alexander von Humboldt Foundation approved my research on “Understanding Anion-pi Interactions: From Supramolecular Assemblies to Proteins.” It was 2011.

I’ll admit, I didn’t have high expectations. I thought I was just taking a wild gamble. But boy was I wrong. This journey led me to a mini-breakthrough as I conducted the first systematic study of all protein structures and discovered that anion-pi interactions, previously known only for simple molecular assemblies, may have a role in biological processes.

Anion-π Interactions in supramolecular assemblies. Source: Wikipedia

What the Heck are anion-pi interactions?

Let me break it down.

First off: “pi” as in the greek letter “π.”

Now, supramolecular chemistry is all about molecular systems that stick together through weak and reversible chemical bonds, like hydrogen bonds, CH-pi, or cation-pi interactions.

In the late 1990s, clever theoreticians did some quantum chemistry calculations and predicted that there could be a counter-intuitive type of bond between anions and aromatic rings, even though anions are negative and aromatic rings are loaded with pi electrons.

“Oh boy, lots of negativity! They shouldn’t attract.”

Yes, that’s what I thought too.

Well, it turns out those predictions were spot on, because in 2004, two different experiments confirmed that anions and aromatic rings do bond via anion-pi interactions in supramolecular assemblies.

That’s where I come in.

I collaborated with one of the groups that showed this interaction exists. Working with Professor Patrick Gamez was a lot of fun. He would bring a question from the experimental side and I would run my calculations to try and answer. It wasn’t easy, but somehow it worked out fine. And the more I dug into the chemistry of anion-pi interactions, the more I thought, “Wait a minute, DNA, RNA, and proteins are packed with aromatic rings, and anions are everywhere. Maybe anion-pi interactions play a role also in biological processes?

So, I joined forces with my colleagues from Berlin and performed the first ever systematic search of the Protein Data Bank to find evidence of anion-pi interactions. We wrote a bioinformatics code to look through thousands of structures for contacts between anions, such as Cl, Br, and PO4, and aromatic amino acids, like tryptophan, phenylalanine, tyrosine, and histidine. If specific geometrical criteria were met, we considered it a potential anion-pi interaction.

We scanned all experimentally known proteins. Well, our code did. And people noticed:

A pioneering systematic search through the Protein Data Bank showed that anion–pi close contacts exist in experimental protein structures between the standard aromatic residues and anions, such as chloride and phosphate

Xavier Lucas – 2016

Indeed, to my amazement, we found that anion-pi contacts meeting the criteria did exist. They were rare, but they existed. And we were right on the money. A couple of months after we published our results, two other scientific articles came out with similar findings.

It’s been a wild ride ever since.

I’ve been keeping tabs on all the scientific articles citing my work and… The field is growing.

Gimme more anion-pi Interactions

Anion-pi interactions are everywhere in RNA molecules. Mohit Chawla & co. found these interactions all over the place, in regular helix structures and between different domains. This means that anion-pi interactions may help maintaining the stability of RNA’s 3D structure.

Anion-pi interactions seem to be key in the functioning of superoxide dismutases, aka SODs. These are like superheroes in our bodies that protect us from harmful oxidative reactions. In fact, some mutations in one type of SOD have even been linked to a neurodegenerative disease. Vesna R. Ribić & co. suggested that anion-pi interactions may support the structural stability of our beloved SODs.

And here’s another one: Anion-pi interactions could also play a crucial role in the development of potential anti-tuberculosis drugs. Let’s not get too excited: Jill F. Ellenbarger & co. in silico data need further confirmation. Yet: pretty exciting, huh?! The team showed that these interactions are involved in the binding between a potential inhibitor and the malate synthase, an enzyme required for Mycobacterium tuberculosis virulence.

Do anion-pi Interactions Really Exist?

Anion-pi interactions were once the black sheep of the chemical world, with many naysayers doubting their significance. They believed, righteously so, that anions and aromatic rings were like oil and water, repelling each other. But after a quarter of a century of digging, research is fervent to demonstrate once and for all that anion-pi interactions should be accepted as the new kid on the (bio)chemistry block.

The importance of anion-pi interactions in biological systems cannot be overestimated. In the last two decades they have turned from controversial to well-established non-covalent interactions of functional relevance in a variety of biomolecules

Mohit Chawla – 2022

A final personal touch

Take a chance, dare to fail, and who knows what adventures you’ll have.

After looking unsuccessfully for the next research job in my cherished Berlin, I was getting ready to leave, but then I thought: “Why not try my wild idea?”

And man, what a jackpot.

My research on anion-pi interactions turned out to be one of my most successful endeavors. I went in with a hunch and ended up with a wild story to tell over a few beers.

Scientific Reading List:

1) Recent advances in anion–π interactions – Robertazzi 2011
2) Anion–π Interactions: Do They Exist? – David Quiñonero 2002
3) Occurrence and stability of anion–π interactions between phosphate and nucleobases in functional RNA molecules – Mohit Chawla 2022
4) Anion–π interactions in active centers of superoxide dismutases – Vesna R. Ribić 2018
5) Anion-π Interactions in Computer-Aided Drug Design – Jill F. Ellenbarger 2018