Ming Li Talk about Bioinformatics


Oct 2, 2013 (3 years and 10 months ago)


Lecture 3.


coil, knobs and hole packing

helix bundle

Donut ring large structure

Globin fold

Ridges and grooves model

CS882, Fall 2006

Packing together, they are stabler

While isolated

helices often occur in proteins, they
are only marginally stable.

They are stabilized by being packed together through
hydrophobic side chains.

We will worry about membrane proteins later.

Project: classify all alpha helix occurrences in the
PDB. In PDB, they tell you which amino acid belongs
to an alpha helix. However, you will need to decide
properly which structure an alpha helix belongs to.

Coiled coil

In 1953, Francis Crick showed that the side chain interactions
are maximized if the two alpha helices are wound around each
other in a “coiled coil” arrangement.

Such structures are the basis of some fibrous proteins, and
others. For fibers, sometimes many hundreds of amino acids to
make long flexible dimmer.

Shorter coiled
coils are also used elsewhere.

Left handed supercoil

from two right
handed helices

The heptad repeat

Number of residues per turn
reduced from 3.6 to 3.5.

The pattern of side chain interaction
repeats every 7 residues, after 2

Such sequence is repetitive with
period 7.

One heptad repeat is labeled a

Residue d is hydrophobic: often a
leucine. Residue a is also

The side chains of e and g (often
charged a.a.) form ionic interactions
between 2 helices

Heptad structure and prediction?

‘d’ residue packs against
each other, ‘a’ residue packs
against each other.

Heptad repeats provide
strong indications of alpha
helical coiled coil structures.

They are found in many
proteins of diverse functions.

Project: predicting such
structures? This not only
helps to predict secondary
but also double helices,
helping 3
D prediction.

Holding up two helices

‘a’ packs with ‘a’, and ‘d’
with ‘d’ (2 levels
squashed view)

The e
g salt bridges
stabilize coiled coil

Just one side of helices,

From e’s to g’s.

Crick’s Knobs and hole model

Alpha helices pack against each other according to knobs and hole

Side chain in the hydrophobic region of one alpha helix can contact
4 side chains from the other helix.

The side chain of the residue at position d is directed into a hole at
the surface of the other helix, surrounded by 1 ‘d’, 2 ‘a’’s, 1 ‘e’, with
numbers n, n
3, n+4, n+1, resp.

Two ‘d’s face each other (usually leucine, isoleucine)







Four helix bundle

Two alpha helices are not
enough to build a domain.

The simplest and most frequent
helical domain is 4 alpha
helix bundle.

Green = hydrophobic residues,
packed inside hydrophobic core;
red = hydrophilic residues.


This appears in many proteins
for oxygen transport, electron
carriers, storing iron atoms, coat
protein for some virus.

Project: predicting 4 helix
bundles? (Collect data first)

4 helix bundle

Usually in 4 helix
bundle adjacent
helices are
antiparallel, such
as in Cytochrome

But other topology
is also possible, as
in Human growth
hormone: two pairs
of parallel helices,
joined in
antiparallel fasion.

Cytochrome b

Human growth hormone

A pair of coiled coils packed with
knobs in holes model

Rop protein has two

Each subunit is an
antiparallel coiled
coil in
which the hydrophobic side
chains are packed against
each other according to the
knobs and holes model.

Two such subunits are
packed according to the
“ridges and grooves” model.

Rop protein

Large and complex ones

Several enzymes are known
to have long polypeptide
chain of 300
400 a.a.
arranged in over 20 alpha
helices packed together in a
complex pattern to form a
globular domain.

Bacterial muramidase:

618 aa.

450 aa at the N
side form a alpha

27 alpha helices

2 layered ring

Diameter 30A

Right handed super twist

The globin fold

This fold has been found in many
related proteins: myoglobin,
hemogobin, light capturing
assemblies in algae, …

Very different from 4 helix bundle,

The 8 helices are connected by
short loop regions, forming a
pocket for active site (this site for
myoglobin and hemoglobin binds
a heme group).

Length varies from 7 (C) to 28 (H)
in myoglobin. Adjacent helices
are not sequentially adjacent
(except for G and H which form
antiparallel pair).

Not from smaller motifs.

Globin fold: 8 alpha helices: A

The white is heme group.

Contains iron

Ridges and grooves model

Ridges every 4

Amino acids

Grooves, between the ridges

Ridges, every

3 amino acids,

counting from a

different angle


A helix.

Each aa

is represented

as one ball.

Treat that as

side chain.

In principle, the

ridges and grooves

are formed by side

chains that are

4 or 3 aa apart,

ridges fit into

grooves, when fold.

How they fit: 25

and 50


aa ridge fit 4

Helix 2 flip over

Superimpose on helix 1

Turn 50
, fit

ridges and grooves

aa ridge fit 4
aa ridge

Helix 2 turn 45

Superimpose on helix 1

Turn helix 2 20
, 4
3 fit.

Evolution: what affects protein fold?

People studied 9 globin structures, trying to figure our what
positions are important for protein to be folded that way.

They choose some “important” positions (functionally, or
structurally) trying to see what made the difference.

They found essentially nothing (including size of amino acids,
matters, except there is a striking preferential conservation of
the hydrophobic character of the amino acids at the buried

On the other hand, at the exposed positions, it actually does not
matter whether we have mutations from hydrophilic to
hydrophobic or vice versa, with one exception: the amino acid 6
in the beta chain in myoglobin (sickle cell disease)

: do this study in a larger class of proteins, and more
carefully. (You can find protein class information at PDB, PFam,
SCOP websites.) Other structures, not just helix?