Transcript Why teach a course in bioinformatics?

Visualizing Protein
Structures
Genetic information, stored in DNA, is
conveyed as proteins
Genetic information, stored in DNA, is
conveyed as proteins
The immediate product of
translation is the primary protein
structure
General Amino Acid Structure
H
H2N
α
C
R
COOH
List of Amino Acids and Their
Abbreviations
Nonpolar (hydrophobic)
amino acid
glycine
alanine
valine
leucine
isoleucine
methionine
phenylalanine
tryptophan
proline
3 letter code
Gly
Ala
Val
Leu
Ile
Met
Phe
Trp
Pro
1 letter code
G
A
V
L
I
M
F
W
P
Polar (hydrophilic)
serine
threonine
cysteine
tyrosine
asparagine
glutamine
Ser
Thr
Cys
Tyr
Asn
Gln
S
T
C
Y
N
Q
Electrically Charged (negative and hydrophilic)
aspartic acid
glutamic acid
Asp
Glu
D
E
Electrically Charged (positive and hydrophilic)
lysine
Lys
K
arginine
Arg
R
histidine
His
H
Others
X = unknown
* = STOP
General Amino Acid Structure
H
H2N
α
C
R
COOH
Peptide Bond Formation
Peptides have rotatable bonds of
defined lengths
Note- all proteins have polarity- N termini; C termini
The ‘protein-folding problem’.
• Proteins -- hundreds of thousands of
different ones -- are the biochemical
molecules that make up cells, organs
and organisms. Proteins put themselves
together, in a process termed "folding."
How they do that is called "the proteinfolding problem," and it may be the
most important unanswered question in
the life sciences.
WHY??
The primary
sequence
dictates the
secondary
and tertiary
structure of
the protein
Protein Structure
Two questions
• Can you change the 3 (tertiary)
o
sequence without changing the 1
(primary) sequence?
o
• Can you change the 1o (primary)
o
sequence without changing the 3
(tertiary) sequence?
What is known about protein
folding?
•
Secondary Structures are
dominated by:
• 1) a-helix
• 2) b-sheet
a-helical structure
is a very regular
structure (3.6
amino acids/turn)
b-sheet: anti-parallel
b-sheet: parallel
Hydrogen Bonding
And Secondary Structure
alpha-helix
beta-sheet
Hydrogen Bonding
• One of the most important stabilizing forces
in protein structure!
• Both a-helix and b-sheet are dependent on
H-bonding.
Protein Folding is progressive?
1° - first
2°- second
3° - third
Formation of tertiary structure
The tertiary structure (or conformation) is the way
alpha -helixes and beta -pleated sheets fold in
respect to each other.
Amino acids which are very distant in the
primary structure might be close in the
tertiary one because of the folding of the
chain.
Structure Stabilizing Interactions
(Factors governing 3° structure)
• Noncovalent
– Van der Waals forces (transient, weak electrical
attraction of one atom for another)
– Hydrophobic (clustering of nonpolar groups)
– Hydrogen bonding
– Salt bridges
• Covalent
– Disulfide bonds
Hydrophobic and Hydrophilic
Interactions:
• Hydrophilic
amino acids are
those whose
sidechains offer
hydrogen bonding
partners to the
surrounding water
molecules.
• Hydrophobic amino
acids:
• Hydrophilic amino
acids:
• Tend to internalize in
water.
• Tend to externalize in
water.
• Tend to externalize in
a membrane
• Tend to internalize in a
membrane
Disulfide Bridge
Disulfide Bridge –
Linking Distant Amino Acids
Structure Stabilizing Interactions
(Factors governing 3° structure)
• Noncovalent
– Van der Waals forces (transient, weak electrical
attraction of one atom for another)
– Hydrophobic (clustering of nonpolar groups)
– Hydrogen bonding
– Salt bridges
• Covalent
– Disulfide bonds
• Protein G Structure Tutorial
• The transformation happens quickly and
spontaneously. It takes only a fraction of a
second for a floppy chain of beads to fold
into the shape it will keep for the rest of its
working life.
• How does that happen? How do the linear
-- and, in some sense, one-dimensional -structures of proteins carry the information
that tells them to take on permanent threedimensional shapes? Is it possible to study
a protein chain and predict the folded
shape it will take?
• That is the protein-folding problem.
DNA sequencing information 
predictions of the primary amino
acid sequence.
Needed- Software that will convert
o
the 1 sequence to its corresponding
o
3 sequence.
Needed- Software that will describe a
o
1 sequence that will generate a
o
particular 3 sequence.
Structure classification:
• Finding proteins that have similar
chemical architectures.
This involves developing a
representation of how units of
secondary structure come together to
form ‘domains’*.
• *compact regions of structure within
the large protein structure.
• The Protein Data Bank
The End
• WHY IS PROTEIN FOLDING SO
DIFFICULT TO UNDERSTAND?
• It's amazing that not only do proteins selfassemble -- fold -- but they do so amazingly
quickly: some as fast as a millionth of a second.
While this time is very fast on a person's
timescale, it's remarkably long for computers to
simulate. In fact there is a 1000 X gap between
the simulation timescales (nanoseconds) and the
times at which the fastest proteins fold
(microseconds).
A Glimpse of the Holy Grail?
• The prediction of the native conformation of a
protein of known amino acid sequence is one of the
great open questions in molecular biology and one
of the most demanding challenges in the new field
of bioinformatics. Using fast programs and lots of
supercomputer time, Duan and Kollman (1) report
that they have successfully folded a reasonably sized
(36-residue) protein fragment by molecular
dynamics simulation into a structure that resembles
the native state. At last it seems that the folding of a
protein by detailed computer simulation is not as
impossible as most workers in the field believe.
Proteins from Scratch:
• Not long ago, it seemed inconceivable that proteins
could be designed from scratch. Because each protein
sequence has an astronomical number of potential
conformations, it appeared that only an
experimentalist with the evolutionary life span of
Mother Nature could design a sequence capable of
folding into a single, well-defined three-dimensional
structure. But now, on page 82 of this issue, Dahiyat
and Mayo (1) describe a new approach that makes de
novo protein design as easy as running a computer
program. Well almost.
Progress in the ‘protein-folding
problem’?
• When proteins fold, they don’t try
ever possible 3D conformation.
Protein folding is an orderly
process (i.e. there are molecular
shortcuts involved).
Success in protein-folding?
Given the primary sequence of a
protein, the success rate in
predicting the proper 3D structure
of a protein shows strong
correlation, to the % of the protein
that showed similarity to proteins
of known structure.
The primary
sequence
dictates the
secondary
and tertiary
structure of
the protein