Báo cáo khoa học: Side-chain control of b-peptide secondary structures Design principles doc

REVIEW ARTICLE
Side-chain control of b-peptide secondary structures
Design principles
Tama
´
s A. Martinek and Ferenc Fu¨lo¨p
Institute of Pharmaceutical Chemistry, University of Szeged, Hungary
As one of the most important families of non-natural poly-
mers with the propensity to form well-defined secondary
structures, the b-peptides are attracting increasing attention.
The compounds incorporating b-amino acid residues have
found various applications in medicinal chemistry and
biochemistry. The conformational pool of b-peptides com-
prises several periodic folded conformations, which can be
classified as helices, and nonpolar and polar strands. The
latter two are prone to form pleated sheets. The numerous
studies that have been performed on the side-chain
dependence of the stability of the folded structures allow
certain conclusions concerning the principles of design of
the b-peptide foldamers. The folding propensity is influ-
enced by local torsional, side-chain to backbone and long-
range side-chain interactions. Although b-peptide foldamers
are sensitive to solvent, the systematic choice of the side-
chain pattern and spatiality allows the design of the desired
specific secondary structure. The application of b-peptide
foldamers may open up new directions in the synthesis of
highly organized artificial tertiary structures with bio-
chemical functions.
Keywords: b-amino acids; foldamers; non-natural polymers;
b-peptides; conformational control; stereochemistry.
Introduction

The macromolecules and ligands responsible for the func-
tioning of living organisms are basically built up from a very
restricted number of building blocks (e.g. a-amino acids and
nucleic acids). Proteins with a propensity to fold into well-
determined hierarchical 3D structures, such as enzymes and
receptors, have developed in nature in an evolutionary time
scale. However, thanks to the tremendous efforts that have
been devoted to the field, scientists now have a clearer
picture of the background to these developments [1,2]. The
principles of protein design are not restricted to the realm of
the heteropolymers of a-amino acids, but can be generalized
and extended to any polymer with a tendency to fold into
the periodic and/or specific compact structures referred to as
foldamers [3,4]. Such foldamers include synthetic oligomers
constructed from b-amino acids as monomers, designated
b-peptides, which are among the most thoroughly studied
and important models in foldamer chemistry.
For the biopolymer community, there are a number
of reasons for the synthesis of b-amino acid-containing
compounds and analysis of their structures. As concerns the
aspects of foldamer design, b-peptides are very close
relatives of a-peptides, their structures containing amide
bonds that allow the formation of stabilizing H-bonds.
Further, the b-amino acids are homologues of the a-amino
acids, the amide groups in the b-peptide backbone being
separated by two carbon atoms. This provides new options
regarding the substituent pattern and the spatiality on C
2
and C
3

with a view to control the secondary structure. The
field of drug design can also benefit from the structural
properties of b-amino acids. The incorporation of b-amino
acids is a successful approach to the creation of peptidomi-
metics with potent biological activity that are resistant to
proteolysis [5–11].
It is interesting that the first b-amino acids were not
produced in scientific laboratories. The conditions on
primitive Earth were such as to lead to the formation of
b-alanine [12] and b-amino acids originating presumably
from comets or asteroids have also been found [13]. Natural
sources too produce b-amino acids [14–17], but reliable and
efficient synthetic routes are indispensable; the relevant
methods have recently been extensively reviewed [18–29].
Despite the availability of reviews on b-peptide foldamers
[30–32], there is increasing interest in the new results and
conclusions, which justifies the present survey on the design
principles.
The conformational pool of b-peptides
It is clear from the general constitution of the b-amino acids
(Fig. 1) that the conformational space can be described in
a very similar way as for the a-residues. According to the
convention of Banerjee and Balaram, the soft torsional
degrees of freedom are defined as CO-N-C
3
-C
2
,C
3
-C

2
-
CO-N and N-C
3
-C
2
-CO designated /, w and h, respectively
[33]. It may be concluded from the presence of the
additional torsion that the increased conformational space
relative to the a-peptides significantly decreases the folding
propensity of the b-peptides, in consequence of the higher
entropy loss [34]. The initial efforts in the laboratories of
Seebach [35–38] and Gellman [39–41] and the increasing
Correspondence to F. Fu
¨
lo
¨
p, Institute of Pharmaceutical Chemistry,
University of Szeged, Eotvos u. 6. Szeged, Hungary.
Fax: + 36 62 545705, Tel.: + 36 62 545564,
E-mail:
(Received 14 April 2003, revised 24 June 2003,
accepted 16 July 2003)
Eur. J. Biochem. 270, 3657–3666 (2003) Ó FEBS 2003 doi:10.1046/j.1432-1033.2003.03756.x
body of high-resolution structural data clearly demon-
strated that b-peptides have an intrinsic propensity to fold
into well-defined periodic structures. Soon after the first
experimental observations, theoretical methods were
deployed to explain the formation of such highly ordered
structures [42–46]. The main conclusion from the ab initio

quantum chemical calculations carried out on blocked
monomers and short oligomers is that the propensity to
form periodic structures with helical symmetry is inherently
encoded in the b-amino acid monomers. Obviously, these
minimal models did not allow an exact quantitative
estimation of the relative stabilities of the possible secondary
structures as a function of the substituent pattern, but the
results did facilitate an enumeration and classification of the
periodic conformations in terms of the /,w,h map (Fig. 2).
The folded b-peptide structures can be classified on the basis
of the grouping of the a-peptide secondary structures [1].
The periodic conformations include various types of helices
and strand-like structures (Fig. 3). The sheet nucleating turn
segments are discussed later. Different designations are
available in the literature for these ordered conformations.
In the present review, we follow the nomenclature intro-
duced by Gellman [31]. In order to avoid ambiguity, it must
be stated that all the periodic structures possess helical
symmetry, but strands will be distinguished from helices on
the basis of the angle of the backbone H-bonds. The
structures stabilized by H-bonds with an angle < 120° are
classified as nonpolar strands, as these conformations may
expose the amide bonds to participation in long-range
interactions, with the formation of pleated sheets.
The b-peptide foldamers have a number of interesting
structural features. The H-bonds stabilizing the periodic
conformations can attain parallel or antiparallel orienta-
tions with respect to the directionality of the b-peptide
chain. The orientation of the H-bonds is closely connected
to the number of atoms comprising the H-bonded ring

Fig. 1. General constitution, definition of the backbone torsions and
designation of the substitution pattern of b-amino acid residues.
Fig. 2. /,w,h representation of the left-handed
uniform periodic conformations of b-peptides.
The selected torsional data were taken from
[22,33–37,43].
3658 T. A. Martinek and F. Fu
¨
lo
¨
p(Eur. J. Biochem. 270) Ó FEBS 2003
formed between the donor and acceptor atoms. For the
structures with 6-, 10- and 14-membered rings, the donor to
acceptor orientation is parallel to the chain directionality on
going from the N-terminal to the C-terminal, while in the
8- and 12-helices and in the 8-strand the orientation is
antiparallel. Besides the novel H-bonding patterns, the sense
of the helix twist can also vary, leading to right-handed or
left-handed helices. Figures 2 and 3 depict only the periodic
conformations with left-handed helicity, but the right-
handed ones can easily be obtained via a mirror operation
that results in /, w-andh-values of opposite sign and
inverted configuration in the event of chiral substitution at
C
2
and C
3
. Apart from the handedness, the size of the
H-bonded ring does not uniquely describe the theoretically
possible periodic structures within the conformational

families of 6-strands and 8-helices. For the left-handed
6-strands, there are three obvious combinations of back-
bone dihedral angles, which can produce periodic structures
designated 6
I
,6
II
and 6
III
following the classification
of Hofmann [47]. The left-handed 8-helices can also be
clustered into two subfamilies: 8
I
and 8
II
. It must be
emphasized that the conformational pool of b-peptide
helical structures is not complete without the experimentally
observed and theoretically studied alternating 10/12 helix
(Fig. 3) [36,37,48]. This conformation has two sets of /,w
angles: /
1
 )90°, w
1
 100°, /
2
 100°, w
2
 )90°,and
auniformh  )60°. These torsions result in an alternating

orientation of the amide groups and thereby a reduced
dipole moment.
Not only the helical conformations are encoded in the
b-amino acid monomers. It has been shown that the torsion
h can occupy an antiperiplanar local conformation that
leads to a strand structure with a tendency to form parallel
and antiparallel pleated sheets [40]. As the amide carbonyls
in this strand point in the same direction, the structure has a
net dipole moment that is fundamentally different from the
situation for the b-sheets formed by the a-peptides, where
the amide bonds point in alternating directions, so that there
is no net dipole.
Following this survey of the conformational pool of
b-peptides, it should be noted that the torsion h cannot
be considered a very flexible conformational degree of
Fig. 3. Backbone geometry of the experiment-
ally observed b-peptide helices and strands with
left-handed helicity. The structures were
modelled by using the representative dihedral
angles depicted in Fig. 2.
Ó FEBS 2003 Control of b-peptide secondary structures (Eur. J. Biochem. 270) 3659
freedom. With a few exceptions, its angle is in most cases
restricted to synclinal (h  ±60°) or antiperiplanar
(h  180°). Accordingly, steps have been taken towards
handling the conformational pool of b-peptides in terms of
the reduced /,w space which is achievable in special cases
[47,49]. However, the reduced representation does not in
general allow a unique description of the various periodic
conformations. For example, the 6
II

-strand and 14-helix
heavily overlap in the /, w map and h is necessary to
distinguish the conformations unambiguously. When the
folded structures with different modes of handedness and
various nonfolded structures are considered [50], the
problems with the reduced representation become even
more severe.
Substituent effects on local geometry
The two carbon atoms in the b-peptide backbone provide
and efficient means with which to influence the intrinsic
secondary structural propensity of b-amino acid residues.
It has been demonstrated persuasively that the secondary
structure motif can be efficiently controlled by altering the
substituent pattern [51,52]. In the approach of Wu and
Wang, the effects exerted by the substituents can be
separated into two groups of components [45]. One
involves the impact on the local conformational stability
at the residue level, referred to as the torsional effect. The
other group comprises the medium- and long-range effects
due to steric and electrostatic interresidue interactions.
The torsional effect of methyl substitution on various
model fragments has been analysed thoroughly by
employing ab initio MO quantum chemical calculations.
The local effect on / of monomethyl substitution at C
3
with the S-configuration [(S)-b
3
-substitution] was studied
in the cases of N-isopropylformamide and N-s-butyl-
formamide, while the influence of (S)-b

2
substitution on
w was modelled with isobutyramide [45] and 2-methyl-
butyramide (Fig. 4) [43]. The potential energy profile of
/ indicates that its allowed values are restricted to the
region between 60° and 180°. There is also a narrow
minimum around )60°, with a relatively high rotational
barrier. The potential energy surface for w was found to
be rather flat, with two minima, in the range 60–180°
and at around )60°. The results can be transferred to
(R)-b
3
and (R)-b
2
substitutions by changing the signs of
the dihedral angles. These analyses reveal that a side-
chainintheb
3
position has a significant structuring
effect on the local geometry exerted through the steric
interactions along /; indeed, the first stable periodic
conformation, the 14-helix, was constructed by using
homochiral b
3
-amino acids. It is interesting to note that
all the H-bond-stabilized periodic structures can be found
within the range / ¼ 60–180° or / ¼ )180–60° that are
in fact the preference regions of the (R)-b
3
or (S)-b

3
,
substituted b-amino acid monomers.
As concerns the nature of the b
3
side-chain, a further
relationship was recognized recently by Raguse et al. [53];
the incorporation of side-chain branching adjacent to the
b-carbon atom stabilizes the 14-helix [54,55]. This effect
may also be explained in terms of the local torsional
effects. Force field calculations suggest (Fig. 5) that, as
the steric demand of the b
3
substituent in the proximity
of the adjacent amide group increases, the conforma-
tional space decreases for the torsion / (T. A. Martinek
and F. Fu
¨
lo
¨
p, unpublished observation). The isopropyl
side-chain corresponding to the (S)-b
3
-hVal residue
significantly increases the energy minimum at )60°,
possibly making this local geometry inaccessible for the
backbone, and narrows the flat minimum at around
120°. For the (S)-b
3
-hLeu model, only the narrowing can

be observed, which is in good accord with the pro-
nounced structuring effect of the b
3
-hVal residues. The b
2
substitution provides a less efficient tool with which to
affect the local flexibility of the torsion w; nevertheless, it
can not be completely neglected.
As was seen above, the appropriate conformation along
the torsion h may be crucial for a certain periodic structure
to be obtained. X-ray and NMR spectroscopic methods
have demonstrated the intrinsic feature of b-amino acids
that the local geometry of h is confined to staggered
conformations (synclinal or antiperiplanar) [46,56,57]. The
local, intraresidue interactions stemming from b
2
or b
3
substitution cannot bring about a prevailing h in solution,
but by means of b
2,3
disubstitution the conformational
preference along the C
2
-C
3
bond can be modulated
successfully. A thorough comparative experimental study
has suggested that the (R,S)-b
2,3

or (S,R)-b
2,3
relative
configuration (Fig. 1) stabilizes the antiperiplanar confor-
mation for h via intraresidue interactions [40], which is a
prerequisite of the polar-strand conformation found in
hairpins as a model of the polar pleated sheet. These
findings were supported by ab initio calculations [58].
Fig. 4. Relative torsional energy profiles for / and w,calculatedfor
(S)-b
3
-Me- and (S)-b
2
-Me-substituted model systems [48]. The reduced
conformational space for both b
3
and b
2
substitution explains their
significant structuring effect.
3660 T. A. Martinek and F. Fu
¨
lo
¨
p(Eur. J. Biochem. 270) Ó FEBS 2003
A noteworthy example of the conformationally constrained
systems is the family of cyclic b-amino acids, where control
of the torsion h is achieved by covalent linkage between C
2
and C

3
[31,39,52]. For these b residues, the antiperiplanar
arrangement (h ¼ 180°) is inaccessible, and the folded
structures with helical symmetry are therefore promoted.
The cyclic b-amino acids may be considered too constrained
to exhibit a real folding reaction [34]; nevertheless, a great
majority of the b-peptide foldamer structures and the
unordered conformations are also accessible with synclinal
conformation at h, and therefore the conformational plas-
ticity is sufficient to allow the folding process. This is
supported by the fact that the cyclic b-residue 2-aminocyclo-
pentane-carboxylic acid (ACPC) can adopt torsion angles
from ± 13° up to ± 90°, which facilitates the fine tuning
of the helix type adopted by b-peptide oligomers construc-
ted from cyclic monomers. The homo-oligomer of trans-2-
aminocyclohexanecarboxylic acid (trans-ACHC) forms a
14-helix, while trans-ACPC adopts a 12-helix, requiring
a larger h to accommodate the increased pitch height
[51].
The covalent restriction of h by employing a cyclic
b-peptide residue combined with the stereochemical tuning
of the preference regions of / and w produces efficient
control over the secondary structure formation [52]. If cis-
(1R,2S)-ACPC is used, the C
2
-C
3
bond can be retained in a
synclinal position in spite of the (R,S)-b
2,3

disubstitution,
which would otherwise lead to an antiperiplanar confor-
mation promoting a polar strand. The (S)-b
3
substitution
forces / into the region 60–180°, while the (R)-b
2
configur-
ation prefers w ¼ ) 60–180°. This set of torsions allows only
an alternating orientation of the amide bonds, which is
present only in the 10/12-helix and in the nonpolar strands.
As the configuration is unfavourable in the 10/12-helix for
steric reasons (see later), the resulting structure is a nonpolar
strand stabilized by weak six-membered H-bonds.
Controlling the backbone to side-chain
interactions
The regions of preference of the local torsion angles may be
perturbed by changing the substituent pattern, but oriented
synthesis of a specific secondary structure can not be
achieved without considering the medium-range backbone
to side-chain interactions, which can override the local
effects. The impact of the side-chain pattern on the
secondary structure preference of b-peptides can be
addressed to a first approximation within the framework
of the ÔfittingÕ theory established by Seebach et al. [37]. The
principle behind this is that any substituent in an axial
orientation relative to the helix axis destabilizes the helical
conformation because of the steric clash between the
substituent and the b-peptide backbone. Thus, the side-
chains occupying axial positions in the helical conforma-

tions push the system to nonpolar strand or polar strand
conformational states. For the left handed 10- and 12-heli-
ces, the substituents R
1
and R
4
are axial, while for the
14-helix, R
2
and R
3
are axial (Fig. 6); thus, any bulky side-
chain in these positions disrupts the formation of the given
periodic conformation. Analysis of the steric interactions,
together with the local torsional effects, allows a finer-
grained analysis of the effects of substituents on the folded
Fig. 5. Relative torsional energy profile for /,
calculated for model systems involving (S)-
b
3
-hAla (S)-b
3
-hVal and (S)-b
3
-hLeu residues
[48]. The calculations show that the strong
structuring effect of the side chains with
branching adjacent to the b-carbon atom
stems from the altered local geometry
preference.

Ó FEBS 2003 Control of b-peptide secondary structures (Eur. J. Biochem. 270) 3661
structures. For example, the 10-helix secondary structure
has not been detected for b-peptide oligomers with
noncyclic side-chains, but only for b-oligopeptides with
strained oxetane side-chains [59], that, in general, suggests
a lower stability for this specific conformation. It is clear
that only substituent R
2
and/or R
3
[(S)-b
3
and/or (S)-b
2
substitution, respectively] is allowed sterically for the left-
handed 10-helix, but at the same time the geometry of the
structure requires / to be in the range )60° to )110°,which
is in the higher energy region of the local torsion energy
profile calculated for (S)-b
3
substitution (see above). The
10-membered, H-bonded pseudocycle, however, can be
found in the 10/12 helix that is preferentially formed by
oligopeptides containing an alternating sequence (S)-b
2
/(S)-
b
3
. These side-chains can occupy the preferred lateral
(equatorial) position in the left-handed 10- and 12-helices

and in the right-handed 14-helix as well, and therefore the
local torsional effect should also be considered. The
unsubstituted C
3
in the first residue allows /
1
to adopt a
dihedral angle of )90°, while the (S)-b
2
side-chain provides a
slight local conformational preference for w
1
that promotes
a dihedral angle of 100°. The second residue with the (S)-b
3
substituent constitutes a strongly preferential configuration
for a torsion /
2
of 100°. Overall, these torsional effects and
side-chain to backbone interactions may contribute to the
observed stability of the 10/12-helix for (S)-b
2
/(S)-b
3
sequences.
The role of long-range side-chain interactions
In folded a-peptide helix design, control of the interactions
between the side-chains separated by a turn of the helix is a
facet of major importance [60,61]. The organizing forces
may comprise the van der Waals and electrostatic inter-

actions. As the circle of synthesizable enantiomerically pure
b-amino acid building blocks widens, a variety of possible
side-chains are available for participation in such stabiliza-
tion [18–29]. Inspection of the 14- and 12-helices (Fig. 6)
reveals that the juxtapositions necessary for the design of
these energy terms are present, while the 10/12-helix lacks
such directly adjacent lateral side-chains (Fig. 7). For the
14-helix, all the b
2
and b
3
substituents with appropriate
stereochemistry are proximal, at positions i and (i + 3).
The adjacent side-chains in the 12-helix are (i)b
3
–(i+2)b
2
and (i)b
2
–(i+3)b
3
.
When the number of possible side-chain interactions and
the pitch height are considered, the conformation most
sensitive to the hydrophobic van der Waals forces is the
14-helix. This suggests that the stability of the 14-helix is
augmented by the solvent-driven attractive forces between
the hydrophobic side-chains. On systematic increase of the
number of possible juxtapositions, extra stabilization can be
observed for the 14-helix at the expense of the 10/12-helix,

but b
2,3
-peptides with all the possible juxtapositions are
destabilized by steric crowding [37]. Unfortunately, it is
Fig. 6. Steric axial side-chain to backbone
interactions and the equatorial juxtapositions
for left-handed 10-, 12- and 14-helices.
According to Seebach’s ÔfittingÕ theory, the
structures display the unfavourable steric
repulsions between the backbone and the
side-chains in axial positions preventing
helix formation. The juxtapositions of the
equatorial side-chains separated by a turn of
the helix allow stabilization by non-bonded
interactions.
Fig. 7. Steric axial side-chain to backbone
interactions and the equatorial juxtapositions
for the left-handed 10/12-helix. As this type of
helix possesses 10-membered and 12-mem-
bered hydrogen-bonded rings in an alternating
manner involving different interaction pat-
terns, the Figure depicts the 10/12 and 12/10
structural motifs separately.
3662 T. A. Martinek and F. Fu
¨
lo
¨
p(Eur. J. Biochem. 270) Ó FEBS 2003
difficult to confirm this trend by conducting experiments in
different solvents with increasing polarity, because the

higher dielectric value and specific interactions scale down
the stabilizing electrostatic forces of mainly H-bonding
origin, which overall counteracts the hydrophobic stabiliza-
tion [55,62,63]. Sensitivity to an aqueous medium is also a
characteristic of the 12-helix [64]. It might be speculated that
H-bond stabilization plays a more important role in
b-peptides than in a-peptides, and this might be the price
for the enlarged conformational space relative to the
number of possible H-bonds [65]. As pointed out by Wu
et al. the dipole–dipole interactions due to the uniform
amide orientation along the backbone are not only a
stabilizing factor, but additionally a source of cooperativity
in the formation of the 12- and 14-helices [66].
As regards the electrostatic interactions between the
side-chains, a useful tool has been developed with which
to increase the stability of the 14-helix even in aqueous
medium. With the choice of a negatively charged and a
positively charged side-chain in the relative positions
i – (i + 3), a salt-bridge can be formed at an appropriate
proton concentration [67,68]. The side-chains of choice
are deprotonated b
3
-hGlu and protonated b
3
-hLys or
protonated b
3
-hOrn, whereby the most effective stabi-
lization can be tailored. A very similar stabilization
strategy of a disulfide lock between the helix side-chains

may be mentioned as an instrument with which to
promote formation of the 14-helix [69]. Although this
establishes a covalent constraint to prevent unfolding and
therefore provides strong stabilization, it could lack the
controlling flexibility of the non-bonded interactions
discussed above.
Nucleation
Certain b-residues or structural motifs have tailored local
conformational characteristics that allow the overall folding
propensity of a given b-peptide to be influenced. This
method of control of the secondary structure formation is
well known in the field of folded a-peptide design and is
referred to as nucleation [1]. An efficient way to improve the
stability of a 14-helix is to incorporate the conformationally
constrained trans-ACHC in the b-peptidic sequence. Even a
single trans-ACHC residue in the central position of the
chain can significantly increase the stability of the 14-helix
[53,70]. A similar 14-helix nucleation effect can be observed
for central (R,S)-b
2,3
or (S,R)-b
2,3
residues [37]. A systematic
study by LePlae et al. revealed that a 12-helix nucleation
effect can be detected on the use of trans-ACPC and trans-
APC (trans-3-aminopyrrolidine-4-carboxylic acid) as con-
formationally constrained residues, and other b
3
-acyclic
side-chains [64]. The 12-helix is still retained in a

b-heptapeptide with only three cyclically restrained residues
in methanol, whereas five constrained residues are necessary
in water.
Interestingly, nucleation of the alternating 10/12-helix
does not require constrained residues; it can be achieved by
using a b
2
/b
3
or b
3
/b
2
dipeptidic sequence [37,48]. Besides
the local torsional preferences (see above), the reason for
this may be that intrinsically the most stable b-peptide
helical structure is the 10/12-helix, because of the advanta-
geous H-bonding geometry [66].
Although the conformational pool of b-peptides allows
polar and nonpolar strand geometries, the propensity to
sheet formation in solution can be studied only by the
construction of simple hairpin (strand-turn-strand) models
as a result of the complexity of the long-range interactions
encountered in sheets. The crucial point here is the synthesis
of the stable turn motif that finally nucleates the pleated
sheet structure. One strategy for sheet nucleation is the
application of conformationally restricted residues in the
centre of the b-peptide chain. An antiparallel sheet-nucle-
ating 10-membered ring was synthesized by employing a
central

L
-proline-glycolic acid segment (Fig. 8A) [40]. The
incorporation of a stabilizing 12-membered ring also
resulted in an antiparallel polar pleated sheet model that
was achieved by using a dinipecotic acid moiety (Fig. 8B)
[71,72]. Another way to nucleate a b-peptide sheet is to take
advantage of the 10-membered, H-bond-stabilized turn-
forming propensity of the b
2
/b
3
or b
3
/b
2
dipeptidic sequence
known from the 10/12-helix. Seebach et al. demonstrated
the feasibility of this approach by using (S)-b
2
/(S)-b
3
residues in the centre of an (R,S)-b
2,3
peptide chain, thereby
creating an antiparallel polar pleated sheet model (Fig. 8C)
[73,74].
Effect of protecting groups
The studies on b-peptide secondary structures mostly cover
chain lengths in the oligomeric region. These relatively short
sequences are rather sensitive to the presence or absence of

terminating protecting groups. It might be considered an
empirical rule in b-peptide foldamer design that removal of
the protecting groups from the C and N termini destabilizes
the 10/12-helix [48], while the absence of the protection acts
as a stabilizing factor for the 14-helix [37]. The best available
explanation is that the protonated N-terminus is in an
advantageous charge–dipole interaction with the relatively
high dipole observed for the 14-helix. This reasoning is
supported by experimental observations on the stabilizing
effect of the helix macrodipole in water [75].
Conclusions and outlook
The peptide sequences constructed from b-amino acid
residues have proved their ability to fold into well-defined
secondary structures. These foldamers cover a wide variety
of periodic conformations comprising various helices, polar
and nonpolar strands and sheets. The b-peptide backbone
with an additional carbon atom provides a well-equipped
toolbox with which to fine-tune the folding propensities of
the sequences, which includes control of the local torsional
interactions, side-chain to backbone interactions, side-chain
to side-chain interactions, and nucleation.
As stated in the Introduction, there are a number of
reasons why b-amino acid-containing compounds can be of
interest to the biochemistry community. We would empha-
size the construction of amphiphilic b-peptide helices with
antimicrobial activity [7]. These foldamers, which have the
propensity to form helical bundles [76,77], have opened up a
new direction towards artificial tertiary structures. The
incorporation of other secondary structural elements will
also hopefully result in new complex structures with useful

functions [78].
Ó FEBS 2003 Control of b-peptide secondary structures (Eur. J. Biochem. 270) 3663
Acknowledgements
The authors’ thanks are due to the Hungarian Research Foundation
(OTKA F-038320, TS-04888) for financial support.
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