The Beginner’s Guide to Protein Folding!

This is a house made of Legos. If you’ve played with Legos, you know they can be used to build a lot of different structures.

I was something of a Lego engineer myself back in the day. But I always wondered, how come if I changed a Lego structure from a house into a a skyscraper, why didn’t it do the same thing? There were both building, which little Lego people were supposed to inhabit. It didn’t make sense!

I soon learned, that if you change the Legos’ shape, you get a completely different structure with a completely different structure and shape.

WHAT DO LEGOS HAVE TO DO WITH PROTEIN FOLDING?

If scientists can figure out the exact methods of protein folding, they will then be able to fold a protein to get it to do anything they want it to do. This could have HUGE implications for the world of biology!!

LET’S BACK UP…WHAT IS A PROTEIN?

How peptide bonds form — through the amino group and carboxyl groups!

The structure of an amino acid looks like this:

We have here a carbon atom attached to a hydrogen in the middle, carboxyl group on the right (COOH), amino group (NH2), and the R group.

The R group is like a remainder of the amino acid: It’s a side chain which consists of molecule which aren’t classified as an amino group or a carboxyl group — they can be elements like chlorine (Cl) or molecules like methyl (CH2). R groups give chemical properties to amino acids.

Proteins have 4 main ways they can assemble:

  • Primary structure: the protein is assembled in a polypeptide chain. This would be like stacking individual Lego bricks to create a tower.
  • Secondary structure: the first step in the folding process.

Alpha helices (formed by hydrogen bonding of the backbone of the amino acid structure) combine with beta pleated sheets (which forms with the same backbone bending over itself to form the hydrogen bonds) in order to give the secondary structure its shape.

A closer look into the structures of alpha helices and beta-pleated sheets.

You can think of this as stacking two Lego towers (one red, one blue) into a chain!

  • Tertiary structure: A protein which gains its 3-D shape primarily due to hydrophilic and hydrophobic interactions (interactions that are attracted and repelled by water respectively) between the R groups. (You’ve now arranged Lego towers into a cube!)
An example of a tertiary folded protein!
  • Quaternary structure: The folding of more than one polypeptide chain. Hydrogen bonds-among other types-are responsible for keeping all of the chains together.
Hemoglobin’s polypeptide chains are being held together by heme groups (includes iron)

This would be like stacking multiple Lego cubes on top of each other and bonding them through KRAGLE / Crazy-Glue (Lego Movie 2014, anyone?)

HOW DO PROTEINS FOLD?

Enzymes known as foldases are also key to the way proteins fold. For example, protein disulfide isomerase is responsible for maintaining the disulfide bonds which give tertiary structures their shape.

PROBLEMS SCIENTISTS ARE CURRENTLY FACING

Unfortunately, there are three main problems that scientists have encountered in this process:

  1. What is the folding code?
  2. What is the folding mechanism?
  3. Can we predict the native structure of a protein from its amino acid sequence?

Back in 1961, Christian Anfinsen discovered that a protein’s amino acid sequence contained the instructions for how to fold a protein in 3D.

Since then, there hasn’t been much advancement.

However, in 2018, a Google-affiliated AI lab called DeepMind used AI in order to predict the most accurate protein folding predictions to date. They trained neural networks to predict the distances between pairs of amino acids and the measures of the angles between chemical bonds which connect these amino acids.

Credit to DeepMind for this animation— this is their technology in action.

In the future, we may be able to use advances in technology like DeepMind’s to help predict protein folding. When we do, you might just have have a protein that can assemble a Lego structure for you!

TL; DR / KEY TAKEAWAYS:

  • Proteins can fold in four types of structures: primary, secondary, tertiary, and quaternary.
  • Protein folding is essential for a protein to perform its job.
  • The Protein Folding Problem poses three main issues: figuring out the folding code, how exactly proteins fold, and if it is possible to even predict how a protein will fold.
  • AI has been used to predict protein folding, thanks to DeepMind.
  • Protein folding can help us better understand how diseases like Alzheimer’s and dementia come about — and potentially how we can refold proteins to prevent diseases.

MORE RESOURCES:

  • This article, published by Chemical & Engineering News
  • DeepMind’s blog post, where they describe in more detail how they went about using their AI to predict protein folding.
  • This article from Why-Sci
  • Pymol, a software for modeling protein folding on a molecular level
  • FoldIt, a cool protein folding video game!

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Hey there, my name’s Apurva! I’m passionate about the applications of genetic engineering, and currently I’m working on human limb regeneration!