Principles of Protein Structure

PHAR 201/Bioinformatics I
Philip E. Bourne
School of Pharmacy & Pharm. Sci.,
UCSD
Prerequisite Reading: Structural Bioinformatics Chapters 12
Thanks to Eric Scheeff and Lynn Fink
PHAR201 Lecture 1 2012

Remember ..
The first 2 lectures are not so much to
teach/refresh your knowledge of
protein/DNA/RNA structure, but for you to
conceptualize, describe and subsequently
analyze complex biological data
Assignment 1 will test this

PHAR201 Lecture 1 2012

Remember..
All which we study is an abstraction to make
comprehension of a complex entity more
straightforward
We think of structures as static entities, but they
are dynamic, sometimes to the point of being illdefinable function requires this flexibility
The more we have the more we should know and
use contrast Kendrew to the PDB today
PHAR201 Lecture 1 2012

Primary Structure - Amino Acids

It is the amino acid
sequence (1940) that
exclusively
determines the 3D
structure of a protein
20 amino acids
modifications do occur
post translationally
PHAR201 Lecture 1 2012

Amino Acids Continued

It is the properties of the R

group that determine the
property of the aa and
ultimately the protein
Different schemes exist for
describing the properties Willie
Taylors scheme is often
employed in bioinformatics
analyses
Hydrophobicity, polarity and
charge are common measures
Learn the amino acid codes,
structures and properties!

Primary Structure

PHAR201 Lecture 1 2012

Amino Acids Continued

Chirality amino acids are

enatiomorphs, that is mirror
images exist only the L(S)
form is found in naturally
forming proteins. Some
enzymes can produce D(R)
amino acids
Think about a data structure for
this information annotation
and a validation procedure
should be included
Think about systematic versus
common nomenclature

Primary Structure

PHAR201 Lecture 1 2012

Peptide Bond Formation

Individual amino acids form a polypeptide chain
Such a chain is a component of a hierarchy for describing
macromolecular structure
The chain has its own set of attributes
The peptide linkage is planar and rigid

Primary Structure

PHAR201 Lecture 1 2012

Geometry of the Chain

A dihedral angle is the angle

between two planes defined by 4
atoms 123 make one plane; 234
the other
Omega is the rotation around the
peptide bond Cn Nn+1 it is
planar and is 180 under ideal
conditions
Phi is the angle around N
Calpha
Psi is the angle around Calpha C
The values of phi and psi are
constrained to certain values
based on steric clashes of the R
group. Thus these values show
characteristic patterns as defined
by the Ramachandran plot

Secondary Structure

PHAR201 Lecture 1 2012

From Brandon and Tooze

Ramachandran Plot
Shows allowed and
disallowed regions
Gly and Pro are
exceptions: Gly has no
limitation; Pro is
constrained by the fact
its side chain binds
back to the main chain

Gray = allowed conformations. A,

antiparallel b sheet; P, parallel b sheet;

T, twisted b sheet (parallel or antiparallel); , right-handed helix; L, lefthanded helix; 3, 310 helix; p, helix.
Secondary Structure

PHAR201 Lecture 1 2012

Secondary Structure
The chemical nature of the carboxyl and amino groups of
all amino acids permit hydrogen bond formation (stability)
and hence defines secondary structures within the protein.
The R group has an impact on the likelihood of secondary
structure formation (proline is an extreme case)
This leads to a propensity for amino acids to exist in a
particular secondary structure conformation
Helices and sheets are the regular secondary structures, but
irregular secondary structures exist and can be critical for
biological function

Secondary Structure

PHAR201 Lecture 1 2012

10

Alpha Helix
A helix can turn right
or left from N to C
terminus only righthanded are observed
in nature as this
produces less clashes
All hydrogen bonds
are satisfied except at
the ends = stable
Secondary Structure

PHAR201 Lecture 1 2012

11

Alpha Helix Continued

There are 3.6 residues
per turn
A helical wheel will
outline the surface
properties of the helix

Secondary Structure

PHAR201 Lecture 1 2012

12

Other (Rarer) Helix Types - 310

Less favorable
geometry
3 residues per turn
with i+3 not i+4
Hence narrower and
more elongated
Usually seen at the
end of an alpha helix
Secondary Structure

PHAR201 Lecture 1 2012

4HHB

13

Other (Very Rare) Helix Types -

Less favorable geometry
4 residues per turn with i+5 not i+4
Squat and constrained

Secondary Structure

PHAR201 Lecture 1 2012

14

Beta Sheets

Secondary Structure

PHAR201 Lecture 1 2012

15

Beta Sheets Continued

Between adjacent polypeptide chains
Phi and psi are rotated approximately 180 degrees from
each other
Mixed sheets are less common
Viewed end on the sheet has a right handed twist that may
fold back upon itself leading to a barrel shape (a beta
barrel)
Beta bulge is a variant; residue on one strand forms two
hydrogen bonds with residue on other causes one strand
to bulge occurs most frequently in parallel sheets
Secondary Structure

PHAR201 Lecture 1 2012

16

Other Secondary Structures Loop

or Coil
Often functionally significant
Different types
Hairpin loops (aka reverse turns) often
between anti-parallel beta strands
Omega loops beginning and end close (6-16
residues)
1AKK
Extended loops more than 16 residues

Secondary Structure

PHAR201 Lecture 1 2012

17

Tertiary Structure
Myoglobin (Kendrew 1958) and hemoglobin
(Perutz 1960) gave us the proven experimental
insights into tertiary structure as secondary
structures interacting by a variety of mechanisms
While backbone interactions define most of the
secondary structure interactions, it is the side
chains that define the tertiary interactions

Tertiary Structure

PHAR201 Lecture 1 2012

18

Components of Tertiary Structure

Fold used differently in different contexts most broadly
a reproducible and recognizable 3 dimensional arrangement
Domain a compact and self folding component of the
protein that usually represents a discreet structural and
functional unit
Motif (aka supersecondary structure) a recognizable
subcomponent of the fold several motifs usually comprise
a domain

Like all fields these terms are not used strictly making
capturing data that conforms to these terms all the more
difficult
Tertiary Structure

PHAR201 Lecture 1 2012

19

Tertiary Structure as Dictated by the

Environment
Proteins exist in an aqueous environment where hydrophilic residues
tend to group at the surface and hydrophobic residues form the core
but the backbone of all residues is somewhat hydrophilic therefore it
is important to have this neutralized by satisfying all hydrogen bonds as
is achieved in the formation of secondary structures
Polar residues must be satisfied in the same way on occasion pockets
of water (discreet from the solvent) exist as an intrinsic part of the
protein to satisfy this need
Ion pairs (aka salt bridge) form important interactions
Disulphide linkages between cysteines form the strongest (ie covalent
tertiary linkages); the majority of cysteines do not form such linkages
Tertiary Structure

PHAR201 Lecture 1 2012

5EBX

20

Tertiary Structure as Dictated by

Protein Modification
To the amino acid itself eg
hydroxyproline needed for
collagen formation
Addition of carbohydrates
(intracellular localization)
Addition of lipids (binding
to the membrane)
Association with small
molecules notably
metals eg hemoglobin
Tertiary Structure

PHAR201 Lecture 1 2012

21

There are Different Forms of

Classification apart from Structural
Biochemical
Globular
Membrane
Fibrous

myoglobin

Bacteriorhodopsin

Collagen

PHAR201 Lecture 1 2012

22

Quaternary Structure
The biological function of some molecules
is determined by multiple polypeptide
chains multimeric proteins
Chains can be identical eg homeodimer or
different eg heterodimer
The interactions within multimers is the
same as that found in tertiary and secondary
structures
PHAR201 Lecture 1 2012

23

Cooperativity

Co-location of
Function
Combination

Structural
Assembly

Quaternary Structure

Hemoglobin:
Enhanced binding
capability of oxygen
Glutamine sythetase:
Controlled use of
Nitrogen from
Multiple active sites
Immunoglobulin:
Multiple receptor
responses
Actin:
Giving the cell shape
and form
PHAR201 Lecture 1 2012

24

Quaternary Structure: Ferritin - The

Bodies Iron Storage Protein

Quaternary Structure

PHAR201 Lecture 1 2012

25

PHAR201 Lecture 1 2012

26

Disorder?

PHAR201 Lecture 1 2012

27

Additional Reading
Branden and Tooze (1999) Introduction to
Protein Structure (2nd Edition) Garland
Publishing.
An excellent introduction

Richardson (1981) The Anatomy and

Taxonomy of Protein Structure Adv. Protein
Chem. 34: 167-339
Good historical perspective
PHAR201 Lecture 1 2012

28