Session 4.1f - Pre-Reading [The Protein Folding Revolution]

Question 1

What do proteins do?

Answer 1

Carry out the labour in our cells.

Question 2

Why is a protein’s shape important?

Answer 2

The key to proteins is their shape because that dictates their function.

Question 3

What shapes can proteins make?

Answer 3

They can take many different shapes.

Question 4

What do scientists call the shapes proteins can make?

Answer 4

Folds

Question 5

What is a protein made up of i.e. what it its base when it is unfolded?

Answer 5

Unfolded, a protein is a long string of amino acids.

Question 6

How many amino acids are there?

Answer 6

20

Question 7

What is significant about each amino acid?

Answer 7

Each one of them has its own chemical behaviour.

Question 8

What happens when a protein folds up?

Answer 8

When a protein folds up, you get a long tangled piece of spaghetti with all these different chemical functionalities on it.

Question 9

How long did it take for a protein’s shape to evolve in nature?

Answer 9

Its 3D shape evolved over billions of years

Question 10

Why did it take billions of years for a protein’s shape to evolve?

Answer 10

They have evolved so they are optimised to do very specific jobs

Question 11

How are proteins optimised to do specific jobs?

Answer 11

Each protein’s 3D shape has evolved over millions of years

Question 12

Why is it important to understand the minute details of the structure of proteins?

Answer 12

If you can understand the minute details of the structure of proteins – not only do you get insights into their function – you might be able to change that function.

Question 13

List two reasons why it is important to understand the structure of proteins?

Answer 13

• understand their function

- to alter their function

Question 14

What is the protein folding problem?

Answer 14

Researchers have been trying for many years to solve the protein folding problem:

“Can we just look at the sequence of amino acids and predict how a protein is going to fold?”

Question 15

How could you predict how an amino acid might fold into a protein using algorithms?

Answer 15

You could take the amino acid sequence, plug it into a computer, and see if your algorithms are good enough to make sense of how it might fold.

Question 16

How can you use imaging to predict how an amino acid might fold into a protein?

Answer 16

You can use X-ray crystallography or other techniques to image a protein structure

Question 17

What is the caveat of using X-ray crystallography to predict how an amino acid might fold into a protein?

Answer 17

You can use X-ray crystallography or other techniques to image a protein structure but that hasn’t been done for very many kinds of proteins.

Question 18

How can protein folding be predicted from genome sequence data?

Answer 18

Could all the genome sequence data – the three billions letters in our genome and the billions in all the other genomes out there – could they scan that code, which is separate from the amino acid code of proteins, and learn anything about how proteins might fold?

Question 19

When did researchers begin to question genome sequencing data in relation to protein folding?

Answer 19

A couple of decades ago (mid 90s)

Question 20

How many letters in our genome?

Answer 20

3 billion

Question 21

How many letters in other species’ genomes?

Answer 21

Billions (generic)

Question 22

What does DNA code for?

Answer 22

RNA

Question 23

What does RNA do?

Answer 23

It is translated into proteins

Question 24

How do we get from DNA to proteins?

Answer 24

The DNA in our genes codes for RNA, which is translated into proteins.

Question 25

How many DNA letters are there?

Answer 25

4 (A C G T)

Question 26

How many amino acid letters are there?

Answer 26

20

Question 27

What is the numerical relationship between the number of DNA letters and the number of amino acid letters?

Answer 27

There’s a relationship between the 4-letter DNA code and the 20-letter amino acid sequences of proteins.

Question 28

How might the 6th amino acid in a sequence end up next to the 18th amino acid in the sequence in a protein (as opposed to the 5th or 7th)?

Answer 28

Because a protein wraps around in many different twists and turns – the 6th amino acid in that chain might end up next to the 18th amino acid.

Question 29

What does it mean for the amino acid sequence if a protein wraps around in many different twists and turns?

Answer 29

The 6th amino acid in that chain might end up next to the 18th amino acid, for example - i.e., an amino acid might not end up next to its sequential amino acid in its fully folded form of a protein.

Question 30

What does it mean if two amino acids in a sequence end up next to each other in the final protein?

Answer 30

If they end up next to each other, researchers realised there might be an interaction between the pair that is critical to the shape of the protein and therefore its function.

Question 31

What does it mean if two amino acids in a sequence end up next to each other in the final protein for the shape of the protein?

Answer 31

There might be an interaction between the pair that is critical to the shape of the protein

Question 32

What does it mean if two amino acids in a sequence end up next to each other in the final protein for the function of the protein

Answer 32

There might be an interaction between the pair that is critical to the shape of the protein and therefore its function.

Question 33

How can mutations of 2 amino acids preserve protein function?

Answer 33

The 6th amino acid in that chain might end up next to the 18th amino acid, for example.

If they end up next to each other, researchers realised there might be an interaction between the pair that is critical to the shape of the protein and therefore its function.

If that’s true then a mutation in the DNA that changes one of the amino acids must be accompanied by another mutation to the other member of the pair to preserve the interaction.

Question 34

What happens if there is a mutation in the DNA that changes one of the amino acids?

Answer 34

The protein is disrupted because interactions to form its final tertiary structure is lost, changing the shape and therefore function.

Question 35

What happens if there is a mutation in the DNA that changes one of the amino acids and also a mutation in the DNA of the amino acid it normally interacts with?

Answer 35

This will preserve the interaction

• a mutation in the DNA that changes one of the amino acids must be accompanied by another mutation to the other member of the pair to preserve the interaction.

Question 36

What is the term used to describe DNA mutations in more than one amino acid that interacts e.g. if the 6th amino acid normally interacts with the 18th amino acid in a chain, but then BOTH of these amino acids endure mutations?

Answer 36

Co-evolve

Question 37

What does it mean for amino acids to co-evolve?

Answer 37

When a mutation in the DNA that changes one of the amino acids is accompanied by another mutation to the other member of the pair to preserve the interaction.

Question 38

How can genome sequences be used in algorithms to predict protein folding?

Answer 38

Well, if you can log maybe a hundred or more of those cases of close-by neighbours in 3D space, based on looking at many genome sequences, then you can plug that into your folding program.

Question 39

What is necessary to know about an amino acid sequence and its subsequent protein before looking at its function (NB: think shape!)?

Answer 39

How the protein and its amino acids appear in 3D space.

Question 40

What is the benefit of notating into an algorithm how proteins fold based on nearby amino acid sequences that interact?

Answer 40

Now that it has all these tight constraints it gives a much better chance of getting a really accurate structure

Question 41

Describe a way that works to predict protein folding

Answer 41

Using genomic sequences to predict amino acid interaction and therefore protein folding

Question 42

Other than accuracy, what is a novel benefit to being able to use genomic sequences to predict protein folding?

Answer 42

The upshot is scientists can fold lots of proteins that they never could before.

Question 43

Why is it important to be able to predict how proteins fold?

Answer 43

That’s important because it will give new insights into how these proteins work.

Question 44

What methods can be used to predict protein folding?

Answer 44

• Amino acid sequence algorithms
• X-ray crystallography (or other techniques)
• Genome data algorithms

Question 45

What are the benefits to using genomic data to predict protein folding?

Answer 45

• ACCURACY in predicted structure
• Many proteins can now be folded that were unable to be visualised before (COMPREHENSIVENESS)
• Gives new insight into how these proteins WORK
• Able to create NEW proteins

Question 46

How have researchers been able to design their own proteins?

Answer 46

Researchers have been steadily improving the ability of computers to model the shape of proteins, and this now enables them to design their own proteins

Question 47

Researchers have been steadily improving the ability of computers to model the shape of proteins.

As well as being able to predict the function of many more new proteins accurately, what else can this be used for?

Answer 47

This enables them to design their own proteins, making things never seen before in nature.

Question 48

What does researchers being able to design their own proteins allow?

Answer 48

Them to make things never seen before in nature.

Question 49

Give an application of researchers being able to design their own proteins.

Answer 49

Medicine

Question 50

Give 2 examples of novel proteins being designed for use in medicine.

Answer 50

• They can target very specific parts of the flu virus with a special built protein – enabling a vaccine that works across flu strains.
• They’ve designed proteins that naturally assemble into tiny cages that can deliver different molecules in the body.

Question 51

How can novel proteins being produced be used to target the flu virus?

Answer 51

Very specific parts of it can be targeted by a special built protein

Question 52

What does targeting specific parts of the flu virus from novel proteins enable?

Answer 52

A vaccine that works across flu strains

Question 53

How can novel proteins be used to deliver different molecules in the body?

Answer 53

Proteins can be designed that naturally assemble into tiny cages

Question 54

Proteins can be designed that naturally assemble into tiny cages.

Suggest ONE application for this.

Answer 54

These can deliver different molecules in the body

Question 55

How can novel protein design be used in surfaces that aren’t biological, e.g. solar cells and electronic devices.

Answer 55

New materials, like engineered surfaces that self-assemble could be used in solar cells and electronic devices

Question 56

Give 2 examples of where engineered surfaces that self-assemble could be used somewhere other than the body.

Answer 56

• Solar cells

- Electronic devices

Question 57

Give 3 examples of how the understanding of protein folding and its application can be used. Include one non-medicinal application.

Answer 57

This information can be used to design new proteins to:

• Target very specific parts of the flu virus with a special built protein – enabling a vaccine that works across flu strains.
• Design proteins that naturally assemble into tiny cages that can deliver different molecules in the body.
• New materials, like engineered surfaces that self-assemble could be used in solar cells and electronic devices

Question 58

Briefly, how does X-ray crystallography work?

Answer 58

• An X-RAY is fired at the protein
• Each PROTEIN CRYSTAL has a unique shape
• The unique shape then causes SCATTERED X-RAYS to form a unique pattern
• This is then detected by an X-RAY DETECTOR
• The detector is connected to a computer to create an image of ATOMS IN PROTEIN CRYSTAL