Applied Bioinformatics

The amino acids

Overview• Proteins (sneak preview)

– Primary structure– Secondary structure– Tertiary structure

• The amino acids– One amino acid– Our first protein– A closer look at the amino acids– Secondary structure preferences

Our goal for today: (a little) understanding of the

relation between amino acids and protein structure

Proteins• Primary structure

– A.K.A. “the sequence”

• Secondary structure– Short stretches form distinct ‘substructures’

• Helices• Sheets• Turns & Loops

• Tertiary structure– The arrangement of secondary structure elements with

respect to each other

Primary structure

Proteins• Primary structure

– A.K.A. “the sequence”

• Secondary structure– Short stretches form distinct ‘substructures’

• Helices• Sheets• Turns & Loops

• Tertiary structure– The arrangement of secondary structure elements with

respect to each other

Secondary structure - α helix

Secondary structure – β sheets

Secondary structure – turns & loops

Proteins• Primary structure

– A.K.A. “the sequence”

• Secondary structure– Short stretches form distinct ‘substructures’

• Helices• Sheets• Turns & Loops

• Tertiary structure– The arrangement of secondary structure elements with respect to

each other

Protein structure (secondary & tertiary) is largely determined by its primary structure.

When you understand the amino acids, you understand everything

The amino acids

A short introduction

One amino acid

- Cα is at the heart of the amino acid- Cα, C N and O are called backbone atoms - R can be any of the 20 side chains

Our first protein

The 20 amino acids

A Ala Alanine C Cys CysteineD Asp Aspartic acid (Aspartate)E Glu Glutamic acid (Glutamate)F Phe PhenylalanineG Gly GlycineH His HistidineI Ile IsoleucineK Lys LysineL Leu LeucineM Met MethionineN Asn AsparagineP Pro ProlineQ Gln GlutamineR Arg ArginineS Ser SerineT Thr ThreonineV Val ValineW Trp TryptophanY Tyr Tyrosine

The 20 amino acidsThe side chains, R, determine the differences in the structural and chemical properties of the 20 ‘natural’ amino acids.

The 20 amino acids can, for example, be classified as follows:

HydrophobicAliphatic Ala, Leu, Ile, ValAromatic Phe, Tyr, Trp, (His)

HydrophilicPolar Asn, GlnAlcoholic Ser, Thr, (Tyr)Charged Arg, Lys, Asp, Glu, (His)

Inbetween:Sulfur-containing Met, CysSpecial Gly (no R), Pro (cyclic)

Several amino acids belong in more than one category.

•There are many ways to characterize the properties of amino acids. The ones most useful and most commonly used are:

•Hydrophobicity•Size•Charge•Secondary structure preference•Alcoholicity•Aromaticity

•And on top of that there are some special characteristics like bridge forming by cysteines, rigidity of prolines, titrating at physiological pH of histidine, flexibility of glycines, etc.

Aromatic

Charged

Sulfur - containing

Really special

Cysteines are extra special

• amino acids don’t fall neatly into classes--they are different combinations of small/large, charged/uncharged, polar/nonpolar properties

• the properties of a residue type can also vary with conditions/environment

Key points about the character of amino acid side chains

Secondary structure preferences

Obviously, there are relations between the physico-chemical characteristics of the amino

acids and their secondary structure preference.

Chou Fasman parameters• Take all protein structures

• Calculate for each secondary structure type how many amino acids are in that structure type (in % of all amino acids)

• Calculate for each amino acid type the distribution across secondary structure types (in % of all amino acids of that type)

• Calculate the preference score

Chou Fasman parameters• Say your dataset is 1000 amino acids and 350 of them are in alpha-helix conformation. • This is 35%.

• There are 50 Alanines in your set and 25 of them are in alpha-helix conformation.• This is 50%.

• The helix preference parameter P for Ala is 50/35=1,43

helix strand turnAlanine 1.42 0.83 0.66 Arginine 0.98 0.93 0.95Aspartic Acid 1.01 0.54 1.46Asparagine 0.67 0.89 1.56Cysteine 0.70 1.19 1.19Glutamic Acid 1.39 1.17 0.74 Glutamine 1.11 1.10 0.98Glycine 0.57 0.75 1.56Histidine 1.00 0.87 0.95Isoleucine 1.08 1.60 0.47Leucine 1.41 1.30 0.59Lysine 1.14 0.74 1.01Methionine 1.45 1.05 0.60Phenylalanine 1.13 1.38 0.60Proline 0.57 0.55 1.52Serine 0.77 0.75 1.43Threonine 0.83 1.19 0.96Tryptophan 1.08 1.37 0.96Tyrosine 0.69 1.47 1.14Valine 1.06 1.70 0.50

©CMBI 2006

Chou Fasman parameters•

Take home message:

• Preference parameter > 1.0 specific residue has a preference for the specific secondary structure.

• Preference parameter = 1.0 specific residue does not have a preference for, nor dislikes the specific secondary structure

• Preference parameter < 1.0 specific residue dislikes the specific secondary structure.

Secondary structure - helix

Secondary structure - helix• Helices pack because of the hydrogen bonds and because of the hydrophobic

packing of side chains along the length of the helix.

• Certain residues do this hydrophobic packing better than others, and those residues are thus good for a helix.

Remember: AMELK

Secondary structure - strands

Secondary structure - strands• Also strands pack because of the hydrogen bonds between the strands and

hydrophobic packing of side chains along the length of the strand.

• Certain residues do this hydrophobic packing better than others, and those residues are thus good for a strands. -branched residues (Ile, Thr, Val) are very good for strands, and so are the large hydrophobic residues.

•

Remember: VITWYF

Secondary structure - turn

Secondary structure - turns• To create a turn the backbone needs to be bent pretty sharply, and some residues

are really good at that.

• Glycine is special because it is so flexible, so it can easily make the sharp turns and bends needed in a -turn. Proline is special because it is so rigid; you could say that it is pre-bent for the turn. Aspartic acid, asparagine, and serine have in common that they have short side chains that can form hydrogen bonds with the own backbone. These hydrogen bonds compensate the energy loss caused by bending the chain into a turn

• Remember: PSDNG

Hydrophobicity

When hydrophobic objects come together in water, the number of unhappy waters go down, and that is good for stability.

Free waters are happy waters.

Hydrophobicity

Hydrophobicity is the most important characteristic of amino acids. It is the hydrophobic effect that drives proteins towards folding.

Actually, it is all done by water. Water does not like hydrophobic surfaces. When a protein folds, exposed hydrophobic side chains get buried, and release water of its sad duty to sit against the hydrophobic surfaces of these side chains.

Water is very happy in bulk water because there it has on average 3.6 H-bonds and about six degrees of freedom.

So, whenever we discuss protein structure, folding, and stability, it is all the entropy of water, and that is called the hydrophobic effect.