This is my “Hello, world!” post. And, I figured I’d start on home turf, with something close to my field of study. It might not be a topic of everyday chatter, but if you’re into engineering marvels, here’s a peek into nature’s own design room.
Throughout my formal education, chemistry mostly meant static 2D formulas driving many-body reactions with the magic lying in the formation of new molecules (no offense to theoretical chemists). I specialized in organic chemistry, and back then, reactions were all I cared about. Then came a major swipe or better yet, a leap – and I ended up working with just single molecules and no reactions at all.
During my Ph.D., I worked with these massive single molecules. And to do what? Study patterns of their movements and flexibility, literally. No reactions, no funny fumes, no green flames – nothing. Just track the vibrations of these giant molecules.
These molecules are called proteins – the currency of survival for you, me, and every living organism on this planet.
They’re among the most fundamental molecules of life, varying in shape, size, and spanning a spectrum of critical biological roles. These molecules do everything: from influencing how young or old you look, to transporting oxygen and carbon dioxide throughout your body, to muscle contraction, to defending against foreign invaders, and more.
But why study their motion? their dynamicity? What’s it really worth?
Naturally occurring proteins are typically made of 20 types of building block molecules called amino acids.These building block molecules differ mainly by their chemical properties like how polar or non-polar they are. So, these protein molecules can be thought of as a tangled thread made of those amino acid beads. Why tangled? Because when tangled, the interactive likeliness between the polar and non-polar amino acids increses. This improved likeness between the amino acids biases the protein molecules to settle into particular shapes. And since the sequence of the amino acids vary from one protein to another, the folded structure also varies accordingly.
There are several experimental techniques like X-ray crystallography, NMR, electron microscopy that reveals protein structures, though mostly in their static forms. “Function follows structure,” a foundational phrase in molecular biology, suggests that a protein’s structure determines how it interacts with other biomolecules inside the cell, such as DNA, RNA, or other proteins, and ultimately enables it to carry out its assigned function. For example, shape of ion transporter proteins, which selectively allows few ions to pass through its tube-like channel, are strikingly different from those proteins that binds to DNA or RNA. Cleary, form must align with function.
But is shape the soul driver of function?
Can a doctor, sitting in a chair calmly, perform surgery to save a dying man? Can you read these words without slightest movement of your pupil? Is a butterfly happy just with having wings, or the joy lie in fluttering them to fly? Exactly the point! Static structure offers only a glimpse into function – it’s the dynamics that truly completes the story.
Conformation of a single protein molecule changes over time generating ensemble (packet of possible states) of different conformations. It’s really all about how the balance between different conformations shifts over time. These changes in populations are what connect structure to function and, ultimately, to life itself. The key idea is that all possible shapes of a protein already exist. So, when a protein does its job, it’s not making a brand-new shape; it’s just tweaking the balance – making certain shape appears more often than others.
Naturally, the long thread made of amino acids, undergoes a self-guided folding process to its native, minimally frustrated, functional conformation.
Why do I mention frustration? Imagine if 100 random individuals are packed into a house to live, peace would be the first to bid farewell. The chaos of unpredictable clashes between different personalities will make the house frustrated. Over time, as mutual understanding improves, would the noise settle into something we may note as harmony. Same for proteins, with hundreds of amino acids tightly packed, countless interactions can happen. This gives rise to a frustrated network of competing forces. Only in the native conformation this frustration is more or less resolved. And that finely balanced state? It’s sculpted by evolution.
Take the Bcl-2 family of proteins, for example. These proteins decide whether a cell should die or stay alive — a role closely tied to cancer biology. They shift shape in fascinating ways to get the job done, like unfolding your hand to pick something up or bending your knees to sit on a chair. But they only do this when they interact with a partner, like another protein or a biological membrane.
Another example is the CRISPR-Cas proteins — the new genie in genetic engineering. These proteins act like molecular scissors, cutting DNA or RNA, but only when they pair with specific genetic material. Otherwise, they remain inactive, doing nothing.
These transformations from ‘doing nothing’ to ‘do something’ is like Bumblebee from the Transformers movie – morphing from car to robot warrior when it’s time for action.
But how does evolution sculpt shape? Why evolution? Because it must adjust the shape in a way that enables the necessary changes in function. And since sequence of amino acid guids the shape, evolution keeps tweaking that sequence through mutations. With these tweaks, out of a pool of possible shapes, certain candidates become dominant. This dominant conformation is then considered the minimally frustrated shape — the one best suited for the required functionality.
However, when proteins evolved to take on a new role, the initial mutations might not get the job done that well. This is because the folded structure isn’t yet optimized, kind of trying out different shapes. Then, over time, further rounds of mutations accumulate to fine-tune the stable conformations and discard the useless ones.
In a laboratory experiment, scientists evolved a protein phosphotriesterase (let’s call it A) into another protein, arylesterase (B). ‘A’ and ‘B’ are different only by means of degrading two different chemical compounds. A key mutation swapped a Histidine for an Arginine, helping B interact with its new target. But Arginine has two shapes- bent and not-bent, and only the bent one works. At the earlier rounds of evolution, both the shapes are existed, so the ‘A’ protein cannot fully become ‘B’ right away. With more mutations, the bent form became stable, and B got better at its job. It’s like learning a dance move — clumsy at first, graceful with practice.
One incredible idea underlying all this is that living organisms are constantly navigating an astronomical number of trials – sorting, filtering and adapting – to perfect every single function needed for survive. And at the heart of it is the fact that a single static structure cannot always explain how proteins actually get things done. It’s not just the form, it’s the motion, the flutter, that gives the power to fly.
For Further Reading:
- Fuzziness and Frustration in the Energy Landscape of Protein Folding, Function, and AssemblyAccounts of Chemical Research, 2021, 54 (5), 1251-1259
Conformational dynamics and enzyme evolution
Journal of The Royal Society Interface, 2018,15(144)
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It tells us the tale of beginning – the most complicated yet the most beautiful of everything – in lucid words and lego-like examples. Loved it.