Protein Structure

Each Protein has a unique

structure

Amino acid sequence

NLKTEWPELVGKSV
EEAKKVILQDKPEAQ
IIVLPVGTIVTMEYRI
DRVRLFVDKLDNIAE
VPRVG

Folding!
 Basic structural units of
proteins: Secondary structure
α-helix β-sheet

Secondary structures, α-helix and β-

sheet, have regular hydrogen-bonding
patterns.
Three-dimensional structure of
proteins

Tertiary structure

Quaternary structure
 Close relationship between
protein structure and its function

Example of enzyme reaction Hormone receptor Antibody

substrates
enzyme A enzyme

Matching
Digestion
the shape
of A!
to A enzyme

Binding to A
 Protein Assembly

•occurs at the ribosome

•involves dehydration
synthesis and
polymerization of amino
acids attached to tRNA:

NH +- {A + B  A-B + H O} -COO -
3 2 n

•thermodynamically
unfavorable, with  E =
+10kJ/mol, thus coupled to
reactions that act as
sources of free energy
•yields primary structure
•
•
Peptide Chain
 Biology/Chemistry of Protein Structure

Primary

Asse m b ly
STRUCTURE

PROCESS


Secondary

Fold in g


Tertiary

Pa ck ing


Quaternary

Int e r a ct ion
 Primary Structure
primary structure of human insulin
CHAIN 1: GIVEQ CCTSI CSLYQ LENYC N •line a r
CHAIN 2: FVNQH LCGSH LVEAL YLVCG ERGFF YTPKT
•or d e r e d
•1 d im e n siona l
•se q ue nce of a m ino
a cid p olym e r
•b y conve nt ion,
w r it t e n fr om
a m in o e n d t o
ca r b oxyl e n d
•a p e r fe ct ly line a r
a m in o a cid
p olym e r is n e it he r
fu nct iona l nor
e n e r g e t ica lly
fa vor a b le 
fold in g !
 Secondary Structure
 non-linear
 3 dimensional
 localized to regions of an
amino acid chain
 formed and stabilized by
hydrogen bonding,
electrostatic and van
der Waals interactions
 Protein Folding
•occu r s in t he cyt osol
•involve s loca lize d sp a t ia l
int e r a ct ion a m on g
p r im a r y st r uct ur e
e le m e n t s, i. e . t h e a m in o
a cid s
•m ay or m ay n ot involve
cha p e r on e p r ot e ins
•t u m b le s t ow a r d s
conf or m a t ions t h a t
r e d u ce  E ( t his p r oce ss
is t he r m o-d yna m ica lly
fa vor a b le )
•yie ld s se con d a r y
st r u ct ur e
 Ramachandran Plot
•Pauling built models based on the following
principles, codified by Ramachandran:
•
(1)bond lengths and angles – should be
similar to those found in individual
amino acids and small peptides
(2) peptide bond – should be planer
(3) overlaps – not permitted, pairs of atoms
no closer than sum of their covalent radii
(4) stabilization – have stericsthat permit
hydrogen bonding

•Two degrees of freedom:

(1) (phi) angle = rotation about N – C
(2) (psi) angle = rotation about C – C
(3)
•A linear amino acid polymer with some folds is
better but still not functional nor completely
energetically favorable  packing!
•
 Protein Packing
•occurs in the cytosol (~60% bulk
water, ~40% water of hydration)
•involves interaction between
secondary structure elements
and solvent
•may be promoted by chaperones,
membrane proteins
•tumbles into molten globule
states
•overall entropy loss is small
enough so enthalpy determines
sign of  E, which decreases
(loss in entropy from packing
counteracted by gain from
desolvation and reorganization
of water, i.e. hydrophobic effect)
•yields tertiary structure
•
•
•
 Tertiary Structure

•non-linear
•3 dimensional
•global but restricted to the
amino acid polymer
•formed and stabilized by
hydrogen bonding, covalent
(e.g. disulfide) bonding,
hydrophobic packing toward
core and hydrophilic
exposure to solvent
•A globular amino acid polymer
folded and compacted is
somewhat functional
(catalytic) and energetically
favorable  interaction!
 Protein Interaction

•occu r s in t he cyt osol, in close p r oxim it y t o

ot he r f old e d a nd p a cke d p r ot e ins
•involve s int e r a ct ion a m ong t e r t ia r y
st r uct u r e e le m e nt s of se p a r a t e p olym e r
cha in s
•m ay b e p r om ot e d b y cha p e r one s,
m e m b r a ne p r ot e ins, cyt osolic a nd
e xt r a ce llula r e le m e nt s a s w e ll a s t he
p r ot e in s’ ow n p r op e nsit ie s
•E d e cr e a se s f u r t h e r d ue t o fur t he r
d e solva t ion a n d r e d uct ion of su r fa ce a r e a
•g lob ula r p r ot e ins, e . g . h e m og lob in ,
la r g e ly involve d in ca t a lyt ic r ole s
•f ib r ou s p r ot e ins, e . g . colla g e n,
la r g e ly involve d in st r u ct ur a l r ole s
Quaternary Structure
•non-lin e a r
•3 d im e nsion a l
•g lob a l, a n d a cr oss
d ist inct a m ino a cid
p olym e r s
•for m e d b y h yd r og e n
b ond ing , cova le nt
b ond ing , hyd r op hob ic
p a ck ing a n d
hyd r op h ilic e xp osur e
•fa vor a b le , f un ct iona l
st r u ct ur e s occur
fr e q ue n t ly a nd ha ve
b e e n ca t e g or ize d
Hierarchical nature of protein
structure
 Primary structure (Amino acid sequence)
 ↓

 Secondary structure （ α-helix, β-sheet ）

 ↓

 Tertiary structure （ Three-dimensional

structure formed by assembly of secondary

structures ）
 ↓

 Quaternary structure （ Structure formed by

more than one polypeptide chains ）
 Class/Motif

•cla ss = se cond a r y st r u ct ur e
com p osit ion ,
e . g . a ll  , a ll  ,
se g r e g a t e d  +  , m ixe d
/
•m ot if = sm a ll, sp e cific
com b ina t ions of se cond a r y
st r u ct ur e e le m e n t s,
e . g .  -  -  loop
•b ot h su b se t of
fold /a r chit e ct ur e /d om a ins
•
•
•
 Fold/Architecture/Domains
•fold = a r ch it e ct ur e = t he
ove r a ll sha p e a nd
or ie nt a t ion of t h e
se cond a r y st r u ct ur e s,
ig n or ing conn e ct ivit y
b e t w e e n t he st r u ct ur e s,
e . g .  /  b a r r e l, TIM
barrel
•d om a in = t h e
f un ct iona l p r op e r t y
of su ch a f old or
a r ch it e ct ur e ,
e . g . b in d ing ,
cle a vin g , sp a nn in g sit e s
•sub se t of t op olog y/fold
fa m ilie s/sup e r f a m ilie s
Topology/Fold families/Superfamilies

•t op olog y = t he ove r a ll
sh a p e a n d conn e ct ivit y of
t he f old s a n d d om a ins
•fold fa m ilie s =
ca t e g or iza t ion t ha t t a ke s
in t o a ccou nt t op olog y a nd
p r e viou s su b se t s a s w e ll
a s e m p ir ica l/b iolog ica l
p r op e r t ie s, e . g .
fla vod oxin
CLASS:  +
FOLD: sandwich •sup e r fa m ilie s = in a d d it ion
FOLD FAMILY: flavodoxin t o f old f a m ilie s, includ e s
e volut iona r y/a n ce st r a l
p r op e r t ie s

•
Protein: The Machinery of Life

NH2-Val-His-Leu-Thr-Pro-Glu-Glu-
Lys-Ser-Ala-Val-Thr-Ala-Leu-Trp-
Gly-Lys-Val-Asn-Val-Asp-Glu-Val-
Gly-Gly-Glu-…..

“Life is the mode of existence of proteins, and

this mode of existence essentially consists in
the constant self-renewal of the chemical
constituents of these substances.”
 Friedrich Engles, 1878