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-Peptides

In recent decade, -peptides, also refered as Nylon-3 derivatives (Mu oz-Guerra et al., 1996 are !ein"
e#tensively e$!raced in $edicinal c%e$istry active peptides and !io$i$etic dru"s. &%ey are enric%in"
our understandin" of t%e enzy$e $ec%anis$s, protein confor$ations, sta!ility and $olecular
reco"nition. &%ey %ave !een proved invalua!le tools as t%ey are co$pati!le 'it% native !iolo"ical
syste$s due to t%eir en%anced potency and re$ar(a!le structural sta!ility a"ainst peptidases in relation
to t%eir counterparts (Gopi et al., )**3+ ,ee!ac% et al., )**1+ -oo( et al., )**1+ .rac(enpo%l et al.,
)**1 . /not%er interestin" aspect of -peptides is t%at t%ey are capa!le of foldin" into 'ell defined and
sta!le %elical, turn and pleated s%eet confor$ations and often display a reverse orientation of t%e
%ydro"en !ondin" pattern vis-a-vis t%eir 0-a$ino acids counterparts.
&%e insertion of additional ato$ (-1-
)
"roup %ere in !et'een t%e peptide units en%ances t%e nu$!er of
de"rees of torsional freedo$, resultin" in an e#pansion of ener"etically accessi!le confor$ational
space. .or e#a$ple, in t%e -a$ino acid residue, local !ac(!one confor$ations are deter$ined !y
value of t%ree torsional varia!les (2, 3, 4 instead of 5ust t'o torsional varia!les (2 6 4 for an 0-a$ino
acid. 7espite t%is increase in t%e fle#i!ility of t%e peptide !ac(!one t%e !uc(lin" of t%e -1-
)
"roups
!et'een t%e 8N- and 819 "roups in t%e polypeptide !ac(!one allo's for t%e retention of t%e
confor$ation for t%e !ac(!one a(in to t%at ac%ieved !y t%e parent structure. Moreover easy $et%ods
are availa!le to ac%ieve t%eir synt%esis (/!del-Ma"id et al., 1999.
-peptides are nonnatural folded poly$ers or folda$ers s%o'in" structural versatility (1%en", )**:
'it% 'ell defined confor$ations and co$prise of a$ino acids, in '%ic% t%eir a$ino "roup is !onded to
t%e car!on (1

instead of t%e 0 car!on as in t%e standard a$ino acids, e#cept "lycine, '%ic% lac(s a
car!on. &%e only naturally occurrin" a$ino acid is -alanine.
;asically, peptides e#ists in t'o $ain for$s+ (i
)
-peptides in '%ic% t%e or"anic residue (< is
positioned ne#t to t%e car!onyl "roup and (ii
3
-peptides, in '%ic% t%e or"anic residue is found ne#t to
t%e a$ine (,ee!ac% and Matt%e's, 199=.
Secondary Structures
peptides represent very versatile structures 'it% "reater diversity in secondary structures t%at can !e
attri!uted to t%eir e#tra 1-1 !ond in >!ac(!one space?. &%ey %ave a ric% confor$ational ener"y space
and sta!le secondary structures unli(e t%e 0-peptides. &%e e#tra-sta!ility of -peptides is renedered !y
t%e a$ide "roups t%at for$ sta!le intra$olecular %ydro"en !onds t%at are for$ed !y t%e %ydro"en
!onded $otifs, '%ic% orient for'ard and !ac('ard to for$ a lar"er variety of %ydro"en !onds. In
"eneral four different secondary structural ele$ents are reco"nized viz. (i zi"-za" (@, (ii %elical (-,
(iii spiral (, and (iv elon"ated (A. 9f t%ese four types, t%e for$er t'o structures reBuire internal
%ydro"en !onds for t%eir sta!ility, '%ile t%e latter t'o structures do not.
(;e(e et al., ()**6, C. 1o$put. 1%e$., )=D )*83E
&%e different confor$ation of peptides 'ere discussed e#tensively in t%e revie's !y 1%en" et al.,
()**1 and Fasudev et al., ()*11. Geptides co$posed of a$ino acids are assi"ned 'it% several
$odels li(e %elices (,ee!ac% et al., 1996+ <a"use et al., )**1, turns (Gade$an et al., )***+ -uc( et al.,
)*** , polar and nonpolar s%eet or strand li(e foldin"s (,ee!ac% et al., 1996+ Harle et al., )**) and
t%ose t%at constitute a $i#ture of !ot% 0 and a$ino acid residues result into distinct folds (,c%u$ann
et al., )***+ ,a"an et al., )**3.
(/ -elices
/ "reater nu$!er of %elical confor$ations are availa!le for peptides. -elical confor$ations of
peptides are a result of polya$ide seBuences co$posed of 1)- andI or 13-su!stituted -a$ino acids
(,ee!ac% et al., 199E and t%e steroc%e$istry deter$ines t%e for$ation of left-%anded
or a ri"%t-%anded %eli#. It 'as noticed t%at only si# or seven (, -a$ino acids are adeBuate to for$
sta!le %elical pattern (,ee!ac% et al., 1996. ,o far, five distinct %elices for$ed !y t%e peptides are
identifiedD 1:, 1), 1*I1), 1* and E--eli#, '%ic% are defined
!y t%e sizes of E-, 1*-, 1)-, and 1:-$e$!ered %ydro"en-!onded rin"s
. &%e no$enclature of t%e peptides %elices is !ased on t%e nu$!er of ato$s in t%e rin" for$ed !y t%e
--!ond.
(i 1:--eli#
,ee!ac% et al. (1996+ )*** %as found t%at -acyclic residues adopt 1:-%elices. Jnli(e t%e <-%eli#, t%e
1:-%eli# %as a 'ider radius, a s%ort rise for a "iven c%ain len"t% and a$ide car!onyl and N- "roups
pro5ectin" to'ard t%e N- and 1- ter$inus resultin" in a net dipole opposite to t%at of <-%eli#. -ydro"en
!onds occurrin" !et'een an a$ide proton at position i and a $ain c%ain car!onyl at position iK) in 1:-
%eli# renders t%e structure sta!le. 9f
particular interest are t%e 13-$onosu!stituted -a$ino acids t%at are for$ed fro$ naturally occurin"
L-a$ino acids !elon" to 3-peptides, '%ic% attain left-%anded 1:-%eli#.
(ii 1)--eli#
9li"o$ers of non-protein-derived a$ino acids are found to fold to ).61)-%elices in crystalline as 'ell
as solvent state '%en t%e su!stituents are positioned at t%e )- and 3-
positions of t%e five-$e$!ered rin" of t%e !eta-a$ino acid s%o'in" an accessi!le di%edral an"le ran"e
in t%e trans-su!stituted
rin" (,ee!ac% et al., )**M. &%e oli"o$ers of t%e cyclopentane-containin"
a$ino acid trans-)-a$ino-cyclopentanecar!o#ylic acid
(/1G1 revealed t%e 1)--elical confor$ation. &%e s$aller rin" size of /1G1 !iases 3 to'ard
lar"er values, renderin" a novel %elical for$, t%e 1)-
%eli#, as t%e $ost favora!le %elical confor$er
. ;ased on t%e 17 and NM< studies, it 'as s%o'n t%at oli"o$ers as fe' as four residues confor$ to
1)--eli# $odel. &%e structure of t%e 1)-%eli# is
sta!ilized !y a series of %ydro"en !onds !et'een
a$ides car!onyl "roups at position i and an a$ide
proton at position iK3 in seBuence. &%e %eli# repeats appro#i$ately every ).M residues and s%o's t%e
sa$e
polarity as t%e <-%eli#, 'it% t%e a$ide protons
e#posed fro$ t%e N-ter$inal end of t%e %eli#. &%e ot%er e#a$ple for 1)--eli# confor$ation of -
peptides is et%anoant%racene-!ased $ono$er (Nin(ler et al., )**1
(iii 1)I1*--eli#
Geptides containin" alternatively !3- and !)-residues
'ere found to for$ a peculiar, ri"%t-%anded ).= 1),1*-%eli# consistin" of alternatin" 1)- and 1*-
$e$!ered %ydro"en-!onded rin"s (,ee!ac% et al., 199=+ Lan"e%an and Gell$an, )**:.
&%e c%aracteristic feature
of t%is %eli# is an intert'ined net'or( of 1*- and 1)-
$e$!ered %ydro"en-!onded rin"s.
-Geptides 'it% alternatin" )- and 3-$onosu!stituted residues adopt t%e 1*I1)-%eli# confor$ation
(,ee!ac% et al., 199=+ 199E.&%e 1*I1)-%eli# is
for$ed '%en residues 'it% interactin"
side c%ains are placed t%ree residues apart. ,urprisin"ly, '%en
considerin" only t%e !ac(!one (oli"o--alanine, t%e
1*I1)-%eli# 'as predicted to !e intrinsically $ore
sta!le t%an t%e 1:-%eli#.
(iv 1*--eli#
1*-%eli#
secondary structure of -peptides is reported for t%e tetra$er of trans-/1-1 in solution (-etenyi et
al., )**M. &%is secondary structure is prepared fro$
$ono$ers 'it% a four-$e$!ered rin" constraint (1larid"e et al, )**1. &%e constitutent
-a$ino acids contain an o#etane rin" (four-$e$!ered rin" et%er and are derived synt%etically fro$
$onosacc%arides
.
(v E--eli#
,%ort oli"o$ers of t%e ac%iral
$ono$er 1-(a$ino$et%yl cyclopropanecar!o#ylic acid
reveal to for$ ei"%t-$e$!ered rin" %ydro"en !onds (/!ele et al., 1999. .urt%er, t%ey also su""ested
t%at lon"er oli"o$ers of t%is type adopt a re"ular E-%eli#, '%ic% constitute appro#i$ately t'o residues
per turn. / related structure %as !een proposed for
oli"o$ers of <-a$ino#y acids (Oan" et al., 1999.
(1%en et al., 1%e$. <ev. )**1, 1*1, 3)19P3)3)

(; -,%eetli(e 1onfor$ations
,$all differences in a$ino acid structure can "ive rise to different secondary structure, '%ic% is
evident fro$ t%e for$ation peptides s%eets. peptides containin" syn su!stituted a$ino acids
separated !y turn-sta!ilizin" residues can for$ s%eets (1%en" et al., )**1. &%ere are t'o types of s%eet
secondary structures for$ed !y peptides, of '%ic% one for$s an anti 1)-13 torsion an"le and anot%er
%as a "auc%e 1)-13 torsion
an"le (6=. In t%e for$er type, all !ac(!one car!onyls are oriented in sa$e direction resultin" 'it% a
net dipole, '%ereas in t%e latter for$ of -peptide s%eet for$ed !y <-peptides %ave little or no net
dipole as t%e !ac(!one car!onyls alternate in
direction alon" eac% strand, si$ilar to t%e -Geptide s%eets for$ed
!y residues 'it% "auc%e 1)-13 torsion an"les
(1 9t%er secondary structures
-peptides also for$ ot%er secondary structure li(e t'isted turns as adopted !y t%e %o$ooli"o$er of
tert-!utyl-di$et%ylsilyl-p%en-
ylisoserine in
c%lorofor$ and revealed !y NM< (16). &%is t'isted strand
confor$ation e#%i!ited !ifurcated %ydro"en !onds in
an intrastrand fas%ion involvin" !ac(!one and side
c%ain functionalities.

&%e structure appears to !e %eld to"et%er !y electrostatic, van der Naals interactions, and !ifurcated
%ydro"en !onds.
Oet anot%er type of secondary structure for$ed !y t%e -peptidesD 9li"o-G1/, oli"o-Nip, and oli"o-
3-%o$oproline and analo"ous to t%e polyproline %elices
is t%e non-%ydro"en !onded structure.
Reference
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.m Chem So!. #$$, Feb %/'%#+(0):%5*#-*
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