Peptoids with aliphatic sidechains as helical structures without hydrogen bonds and collagen/ inverse-collagen type structures

doi:10.4236/jbpc.2011.21006

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Vol.2, No.1, 37-48 (2011) Journal of Biophysical Chemistry

doi:10.4236/jbpc.2011.21006

Peptoids with aliphatic sidechains as helical structures

without hydrogen bonds and collagen/ inverse-collagen

type structures

Fateh S. Nandel, Avneet Saini

Department of Biophysics, Panjab University, Chandigarh, India; fateh_nandel@yahoo.com

Received 29 September 2010; revised 30 October 2010; accepted 12 November 2010.

ABSTRACT

Aliphatic homo-polypeptoids of NAla, NVal, NIle

and NLeu both in the presence and absence of

protecting groups adopt helical structures

without hydrogen bonds with Φ, Ψ values of ~ 0,

± 90° with trans amide bonds. These structures

are stabilized by carbonyl-carbonyl interactions

and characterized by ~ 3.16 residues per turn

with a pitch of ~ 6.13 Å. It has been shown that

like polyvaline and polyleucine peptides, poly-

peptoids can also be exploited for the con-

struction of potential surfactant like molecules

by incorporating charged amino acid residues

at the N terminal. A single-handed template with

Φ, Ψ values of ~ 0, 90˚ can be attained by in-

corporating L-leu or L-val at the C-terminal of

poly-NIle. Analysis of the simulation results in

water as a function of time reveals that the

opening of helical structures without hydrogen

bonds takes place at sub-picosecond time scale

starting from the N-terminal. This leads to the

formation of collagen or inverse-collagen type

structures (Φ, Ψ ~ -60, 145˚ and 60, -145˚ re-

spectively) stabilized by interactions of water

molecules with the backbone carbonyl groups.

Keywords: Peptoids; Conformation; Hel i cal

Structure without Hydrogen Bonds; Collagen and

Inverse-Co llagen Type Structures

1. INTRODUCTION

Design of polymers and oligomers that mimic com-

plex structures and biological properties of proteins is an

important endeavor with both fundamental and practical

implications as polypeptides themselves are generally

poor drugs, due to their in vivo rapid degradation by

proteases and their immunogenic character [1,2]. To ad-

dress multiple design criteria for applications ranging

from medicinal chemistry to material science, focus is to

identify non-natural chemical scaffolds that recapitulate

the desirable attributes of polypeptides i.e. peptidomi-

metics. These should have good solubility in aqueous

solution, access to facile sequence specific assembly of

monomers containing chemically diverse side chains and

capacity to form stable structures.

‘Peptoids’ offer attractive peptidomimetics [2] as their

backbone is similar to that of peptides. Shifting of the

side chain to the main chain nitrogen atom, shown in

Figure 1, renders the alpha carbon achiral. Peptoid mo-

nomers are linked through polyimide bonds and lack the

amide hydrogen; precluding the formation of hydrogen

bond networks that stabilize peptide secondary structures.

Their conformational behavior can be related to both

proline and glycine residues. These modifications be-

stow protease resistance [3], while allowing suitable

mimicry of the spacing between the critical chemical

functionalities of bioactive peptides. Thus, it remains to

be an area of active research for conformational investi-

gations, analysis of interactions and hence, designing of

molecules. In addition, the efficient sub-monomer solid

phase synthesis gave a major breakthrough in peptoid

research, due to the access to a large number of diverse

primary amines that can be added and that too at low

costs [4].

Consequently, peptoids have found application as: i)

Figure 1. Primary structure of peptoid.

F. S. Nandel et al. / Journal of Biophys ical Chemistry 2 (2011) 37-48

attractive targets for the drug discovery process [5], ii)

motif for combinatorial strategies [5-10], and iii) to de-

velop peptide mimics for biomedical applications

[11-17]. They have also been exploited for their cell pe-

netrating properties [18] and antifouling action on sur-

faces [19,20]. New approaches to direct the peptoid

backbone towards formation of specific secondary

structures such as helices (a structure in which residues

rotate and rise in a repeating manner along an axis, but

of what type?) are being explored for the discovery of

bioactive peptoid modules [21-26].

In spite of their various applications limited system-

atic structural/conformational data is available on pep-

toids [27-29]. Peptoids comprising of 100% achiral,

aromatic NPhe side chains displayed no net CD. It is not

clear whether the no net CD signal is a result of degen-

erate conformations of opposite handedness or other

structures adopted by the peptoid. It may be mentioned

that even systems having no chiral centers can adopt

well defined helical structures. Peptoids containing

chiral aromatic side chain i.e. NSpe is strongly reminis-

cent of the alpha-helical signal on the basis of CD signa-

tures that are almost similar to that of α-helices in pep-

tides [30,31]. On the other hand NMR and CD studies on

peptoids containing α-chiral aliphatic side chains have

shown features similar to those of polyproline type heli-

ces [28]. On the basis of CD spectroscopic results it is

even proposed that α-chiral aliphatic and α-chiral aro-

matic sidechains form helices of essentially the same

type.

Thus, the conformational behavior of peptoids and the

secondary structure adopted by them remains an active

area of research. In this study we report the conforma-

tional preferences of both homo- and hetero-polypepto-

ids of the type; Ac-(NXaa)n-NMe2 of varying chain

length where ‘NXaa’ is a peptoid residue with the amino

acid side chain attached to the amide nitrogen atom by

keeping the amide bond geometry both as trans or cis.

The conformational results thus obtained, shall aid in the

construction and design of peptoid based biomimetics.

2. METHODOLOGY

Knowledge about the global, local and low energy

minima for the peptoid models Ac-NXaa-NMe2 was

obtained from the Φ, Ψ maps and  potential energy

curves that were constructed using standard bond lengths

and bond angles. Input for peptoids was given in terms

of internal co-ordinates i.e. bond lengths, torsion angles

and connectivity of the atoms. Energy calculations were

carried out using the semi-empirical quantum mechani-

cal method PCILO (Pertubative Configuration Interac-

tion using Localised molecular Orbitals) [32] and mini-

mization was done by the variation of torsion angles.

The various conformational states of all constructs were

generated based on the global, local and low energy mi-

nima in the Φ, Ψ maps and i, j curves/maps of model

peptoids and their energies computed. Minimization was

further refined by varying Φ, Ψ, ω and  values in the

neighborhood of the minima in steps of 5/2 degrees.

Minima obtained by PCILO calculations are also the

minima at the ab initio level for the usual amino acids

[33] and for dehydroamino acids [34-36]. In addition the

PCILO results [37,38] for the peptides containing usual

and unusual amino acids are in conformity with ab initio

results [39,40] and knowledge based crystallographic

data [41,42]. The charges on various atoms in different

conformations of peptoid models were computed using

the GRINDOL method [43].

Molecular Dynamic (MD) simulations provide great

deal of information regarding the stability of peptoids in

water and to the mobility of the peptoid residues. The

results obtained by quantum mechanics calculations

were used as the starting geometries for simulation stud-

ies using GROMACS 3.3.1 MD software package [44].

The Dundee-PRODRG2 [45] server was used to obtain

the GROMACS topology and coordinate files. Interac-

tion parameters within the design sequence were taken

from GROMOS-96 force field G43a1 [46]. It is worth

mentioning that the simulation results obtained by

GROMOS force field are in good agreement with the

experimental results [29,47 and 48]. Energy of the sys-

tem was minimized by the steepest descent method, us-

ing the convergence criteria of 50 kJ mol-1 followed by

conjugate gradient method with a force constant of 20 kJ

mol-1. Next, the MD run was carried out in vacuum for

20 ns, with a time step of 2 fs using the Leap Frog Algo-

rithm. The temperature was controlled through weak

coupling to a bath of constant temperature [49], using a

coupling time; τp of 0.1ps and a reference temperature;

T0 of 300 K. LINCS algorithm [50] was used to restrict

all bonds to their equilibrium lengths and the center of

mass motion of the system was removed every step to

maintain the effective simulation temperature at 300 K.

For the evaluation of coulomb interactions and Van der

Waals interaction a cut off of 0.9 and 1.0 nm respec-

tively was applied. Long range forces were updated

every 10 fs during generation of the neighbor list. The

Long Range Electrostatic Interactions were calculated

using a Particle Mesh Ewald Summation. Initial veloci-

ties of all atoms were taken from a Maxwellian distribu-

tion at the desired initial temperature. After the vacuum

MD simulation a simple cubic periodic box was set up

using the Simple Point Charge (SPC) Water Model [51].

In order to allow equilibration of solvent around the

model sequence, position of all peptoid residues was

restrained for 20 ps. Finally, MD simulation for 1ns at

300 K, without any restrictions was carried out. The

F. S. Nandel et al. / Journal of Biophys ical Chemistry 2 (2011) 37-48

Table 1. Conformational results* of the various dipeptoid models.

Φ, ψ, ω ΔE Φ, ψ, ω ΔE Φ, ψ, ω ΔE Φ, ψ, ω ΔE

χi, χj (deg) kcal/mol χi, χj (deg) kcal/mol χi, χj (deg) kcal/mol χi, χj (deg) kcal/mol

Ac-NAla-NMe2 Ac-NVal-NMe2

–2, 92, 180 0 –175, 85, 0 1.8 0, –85, 174 0 100, 135, –3 –1

175 75

–5, –80, 180 0 180, –95, 0 3.7 0, 90, 174 0.4 –70, 170, –10 0.7

175 120

180, –90, 180 1.8 –95, –170, 175 1.5

135

180, 90, 180 1.9 85, 175, 170 2.1

110

120, 180, 180 2

–120, 180, 180 2.4

Ac-NLeu-NMe2 Ac-NIle-NMe2

15, –105, 180 0 –125, –170, 03.2 5, 85, 180 0 –95, –155, 0 2.5

130, 175 –65, 175 145, 170 155, 180

15, 70, 178 1.5 120, –175, 03.5 0, –90, 180 0.3 90, 180, 0 5.2

130, 175 65, 70 145, 170 155, 180

120, 180, 180 2.6 –60, 175, –54 –90, 180, 180 2.9

–110, 55 115, 180 145, 170

–120, 180, 178 2.9 55, –160, 8 4.2 90, 180, 180 4

–5, –60 –115, 60 145, 170

* Φ, ψ values are in bold, ω in italics and χi, χj in normal text.

pressure was controlled using weak coupling with a time

constant of 0.5 ps and a reference pressure of 1 Bar.

3. RESULTS AND DISCUSSION

Conformational results in terms of Φ, Ψ, ω and χ val-

ues of the various model dipeptoids in both cis and trans

amide bond geometries are summarized in Table 1. In

general, there is not much difference in the energy of the

various conformers and hence, with a change in experi-

mental conditions different states may be populated.

Results in Table 1 also reveal that NAla can be popu-

lated in several conformations due to its simple and

small side chain with no branching. Thus, incorporation

of NAla in peptides may lead to disruption of helices as

the energy difference between the states is small and

different states may be populated depending on the en-

vironment. This observation is consistent with the ex-

perimental finding that incorporation of NAla in the oth-

erwise helical antimicrobial peptides decreases the heli-

cal content [52].

In higher mers of all peptoid models it is apparent

from the results in Table 2 that degenerate helical struc-

tures without hydrogen bonds with Φ, Ψ values of ~ 0, +

90˚ are most stable with trans amide bond geometry.

These structures characterized by n = 3.16, with a pitch

of 6.13 Å have also been reported in poly-dehydro ami-

no acids [36]. A molecular view of the models Ac-NVal7-

NMe2 and Ac-NIle7-NMe2 shown in Figure 2 with trans

amide bonds for the conformational states with Φ, Ψ

values ~ 0, -90˚ and 0, 90˚ respectively clearly shows

pore formation with an average diameter of 4.6 Å with

hydrophobic side chains protruding outwards. Such

structures are maximally stable in the hydrophobic en-

vironment masking the carbonyl oxygens that point in-

wards towards the central cavity. Negative charge on

carbonyl oxygen (~ -0.66) may provide a negative po-

tential gradient along the pore facilitating the cation to

F. S. Nandel et al. / Journal of Biophys ical Chemistry 2 (2011) 37-48

Table 2. Conformational results* for homo-polypeptoid models.

ΔE Φ, ψ,

ω χi, χj (deg) kcal/mol˚

1 2 3 4 5 6 7

Ac-NAla6-NMe2

–15, 105, 178 –25, 120, 173 0, 90, 172 –25, 110, 170 –5, 95, 176 0, 95, 170 0

- - - - - -

5, –95, –179 15, –100, –178 10, –95, –179 15, –105, 180 5, –95, –174 10, –100, –179 0.17

- - - - - -

Ac-NVal6-NMe2

0, 90, 178 –10, 100, 176 –5, 95, 172 –5, 95, 174 –5, 95, 172 –5, 95, 176 0

90 95 95 90 95 90

–5, –85, –176 5, –95, –172 5, –95, –172 5, –95, –172 5, –95, –172 5, –95, –176 0.66

90 145 145 150 145 150

–90, 180, 178 –85, 175, 178 –95, –175, 178 –65, 170, 176 –80, 175, –178 –40, 135, 178 19.53

135 130 150 120 125 125

90, –175, –178 90, 175, 180 85, 180, –176 95, 170, –176 85, 180, –176 45, –145, –178 19.55

100 100 115 100 115 120

NVal6-NH2

–, 180, 176 0, 90, 172 –10, 100, 170–5, 95, 170 –10, 100, 172 0, 90, –176 0

–170 155 95 95 95 90

–, 175, –178 0, –90, 180 30, –120, –174–5, –90, –17630, –120, 1800, –90, 174 0.72

40 145 145 85 145 90

Ac-NLeu6-NMe2

5, 85, 176 5, 90, 170 5, 90, 168 10, 85, 172 0, 90, 176 –5, 95, 176 0

130, 175 120, 180 120, 175 115, 175 115, 175 115, 180

25, –115, –177 30, –120, 172 30, –120, 17735, –120, 174 30, –120, 170 15, –100, 173 3.84

130, 175 85, 75 90, 75 90, 75 90, 80 85, 85

Ac-Nile7-NMe2

5, 85, 174 –5, 95, 172 –5, 95, 172 –5, 95, 174 –5, 95, 172 –5, 95, 176 0, 90, 176 0

150, 165 95, 170 95, 175 90, 170 90, 175 90, 170 95, 170

0, –90, –178 5, –105, –174 5, –95, –174 10, –100, –174 –5, –90, –16630, –120, –174 5, –95, –178 0.25

110, 55 150, 170 150, 165 150, 170 145, 165 140, 170 85, 170

Ac-NLys-NLeu6-NMe2

–90, 160, 180 5, 90, 170 0, 90, 178 10, 85, 180 0, 90, 176 –5, 95, 176 0, 90, 180 0

180, 180, 160, –175 120, 180 120, 175 115, 175 115, 175 115, 180 120, 180

* Φ, ψ values are given in bold, ω in italics and χi, χj in normal text.

pass through in a single file. Thus, like Grami-

cidin A, these peptoids may be exploited for the con-

struction and design of channels in membranes. It is also

obvious from the results in Table 2 that presence or ab-

sence of protecting groups hardly affected the nature of

the most stable conformation adopted by poly-NVal.

These helical structures without hydrogen bonds are

stabilized by carbonyl-carbonyl interactions between

carbonyl oxygen of ith residue and carbonyl carbon of

ith + 1 with dOi…Ci+1 being 2.18 Å. A careful look at the

data from penta peptoid onwards revealed that in the

conformation with Φ, Ψ values of ~ 0, 90˚ all ω values

lie between 168 ≤ ω ≤ 180˚ and in the conformation with

Φ, Ψ values of ~ 0, - 90˚ they lie between 180 ≤ ω ≤

194˚.The deviation in ω values resulted in stronger car-

bonyl interactions relative to those in complete trans

amide bond geometries. In addition, C-H…O interac-

tions between the C = O of ith residue and HCα-N of the

side chain of ith + 3 residue (dO…H and dO…C being ~ 2.1

and 3.0 Å) leads to the formation of an eleven membered

ring (Figure 2). Based on a systematic study between

ketonic groups in the Cambridge structure database car-

bonyl-carbonyl interactions [53,54] have been modeled

by three main types of interaction motifs. Importance of

carbonyl interactions as a stabilizing factor in α-helices,

β-sheets and right-handed twist is well-documented [55,

F. S. Nandel et al. / Journal of Biophys ical Chemistry 2 (2011) 37-48

Figure 2. Molecular view of (a) Ac-NVal7-NMe2 in the con-

formation state with Φ, Ψ, ω values of ~ 0, -90, 180˚depicting

carbonyl-carbonyl interactions and formation of an eleven

member ring due to C-H…O interactions between the ith and ith

+ 3 residue; (b) Ac-NIle7-NMe2 with Φ, Ψ , ω values of ~ 0, 90,

180˚showing the formation of a hydrophilic pore with the

masking of the carbonyl groups by the hydrophobic side

chains.

56]. They also stabilize the partially allowed Ramachandran

conformations of aspartic acid and asparagines [55] and

helical structures without hydrogen bonds in peptides con-

structed from achiral and unusual amino acids [36,58-59].

Degenerate helical structures without hydrogen bonds

with opposite handedness observed in polypeptoid mod-

els of NVal/NIle having branching at the N-Cα position

implies population of both states to the same extent and

hence, very well explains the very weak/no signal in CD

spectroscopy for aliphatic peptoids [28]. Interestingly,

for poly-NLeu only one state with Φ, Ψ values of ~ 0, 90

° is predicted; possibly due to the side chain branching at

the N-Cβ position. Thus, the difference in the branching

pattern changes the local environment and may be re-

sponsible for the difference in the conformational be-

havior of peptoid models.

Φ, Ψ values of 0,  90˚ appear to be unusual even in

peptides, but this region has been predicted a minima for

some amino acids [36]. Also, for the dipeptides of glycine

& alanine [60] a stationary point near Φ = 0˚ , Ψ = 90˚ at

the HF/3.21G and HF/6.31+G levels has been reported.

Ramachandran plots based on; i) PDB- 40 dataset [61]

corresponding to X-ray protein structures with the resolu-

tion of 2.5 Å or better for 470 proteins, 95778 total resi-

dues plotted, proline and glycine excluded and (ii) NMR

derived structure for 113 proteins, 84719 total residues

plotted, (proline and glycine excluded) show appreciable

density between the left-handed helical region and the

collagen-type structural region [62,63] and between the

right-handed helical region and the inverse-collagen type

structural region [60,61]. Though, the dataset for the

NMR derived structures is small compared to the X-ray

protein structures, yet in the mentioned regions the data

point density is more for NMR derived structures i.e. in

the solution phase. Thus, the conformational states with Φ,

Ψ values of ~ 0,  90˚ are not an over-estimation and may

be realized in solvents with low polarity.

4. CONSTRUCTION AND DESIGN

OF NANO-STRUCTURES

Single Handed Template: Alipihatic polypeptoids

were realized in degenerate helical structures without

hydrogen bonds with rise & rotation per residue of 1.94

Å and 114˚ respectively. To construct a template with a

given handedness from these peptoid residues, either

L/D-Leu or L/D-Val residue was incorporated either at

the N-terminal or the C-terminal of the poly Nile/Nval

peptoid sequences of required length. Incorporation of

such chiral amino acids has been shown to control the

screw sense of helical peptides constructed from achiral

residues [36,58,62-63]. Therefore, these amino acids

(L/D-Val or L/D-Leu having branching in the side chain)

were incorporated in achiral peptoids to control the screw

sense of helical structures. The conformational results

thus obtained are given in Table 3 and it is obvious that

in poly-Nile peptoid models the degeneracy was lifted

and only one conformation with Φ, Ψ values of ~ 0, 90˚

was realized by incorporating L-leu or L-val at the

C-terminal. Incorporation of L or D-leu either at the N or

C-terminal of poly-NVal sequence models did not lift the

degeneracy. This may be attributed to the local environ-

ment around N-Cα, which is asymmetrical in NIle resi-

dues and symmetrical in NVal residues. Thus, NIle with

its asymmetrical side chain plays a vital role in lifting

the degeneracy and hence, construction of a single

handed template.

Peptoids as Surfactants: The helical structures

adopted by homo-polypeptoid models (NVal, NLeu, NIle)

appear similar (although with different Φ, Ψ values) to

the corresponding helical structures in polypeptides of

leucine, valine, isoleucine and norleucine with the

non-polar side chains projecting outwards forming

well-defined hydrophobic structures with a hydrophilic

pore. Poly-leucine, poly-valine, poly-isoleucine and

poly-norleucine like peptides have shown surface activ-

ity that helped in accelerating the surface spreading at

the air-water interface and thus, exhibited improved dy-

namic activity. Poly-leucine peptides or peptides rich in

leucine have been exploited for their surfactant like

properties especially in lung surfactant proteins SP-B

F. S. Nandel et al. / Journal of Biophys ical Chemistry 2 (2011) 37-48

Table 3. Construction of a single handed template for Ac-L-leu-(NIle)6-NMe2.

Φ, ψ, ω

χi, χj (deg)

ΔE

kcal/mol

1 2 3 4 5 6 7

Ac-L-leu-(NIle)6-NMe2

–100, 130, –92 10, 80, 176 0, 95, 170 –5, 95, 172 –5, 100, 172 –5, 95, 172 0, 90, 174 0

–55, 170 155, 170 90, 175 95, 175 95, 175 95, 170 90, 175

–155, 150, 90 0, –90, –178 –5, –90, –172 5, –95, –176 25, –120, –174 0, –90, –176 0, –90, –178 1.99

55, 150 150, 170 155, 160 150, 170 150, 170 90, 170 150, 170

Ac-(NIle)6-L-leu-NMe2

15, 90, 90 0, 95, 170 0, 95, 170 –15, 100, 1760, 90, 172 15, 70, 178 –20, 115, 174 0.68

140, 170 100, 170 95, 170 95, 165 90, 170 90, 175 –65, 170

–10, –80, –86 10, –100, –178 0, –95, –170 25, –120, –1760, –90, –176 –5, –75, 176 180, 160, –178 7.00

130, 50 145, 175 150, 165 140, 175 90, 170 155, 170 60, 140

Ac-(NIle)6-L-val- NMe2

5, 85, 178 –5, 100, 170 5, 90, 166 –15, 100, 176 0, 90, 172 5, 75, –176 –10, 105, 174 0

145, 170 90, 170 100, 165 90, 160 90, 170 90, 170 180

–5, –85, –178 15, –105, –176 0, –95, –166 0, –95, –170 0, –90, –172 –5, –75, 176 –30, 115, –170 3.56

115, 60 145, 170 150, 170 150, 160 150, 170 155, 170 50

and SP-C [13,14]. On similar lines the corresponding

peptoid mimics are constructed to design surfactant like

molecules by incorporation of NLys residue at the

N-terminal in poly-NLeu and the conformational results

are summarized in Table 2. A graphical view of the

peptoid in the most stable state as shown in Figure 3

clearly depicts that NLys residue resembles the polar

head group and the NLeu residues formed the hydro-

phobic tail like structure similar to that of lipids.

5. SIMULATION STUDIES

Simulation studies on aliphatic peptoids reveals almost

Figure 3. A graphical view of the surfactant peptoid design

‘Ac-NLys-(NLeu)6-NMe2’.

similar conformational results irrespective of the initial

geometry taken for simulations (i.e. with Φ, Ψ = 0, 

90˚ ;  60, 180˚ ; or  120, 180˚ ) and the side chain.

This means shifting of the side chain from the carbon

alpha to the amide nitrogen makes the peptoid backbone

less flexible and this observation is consistent with the

experimental and computational results [29,64-65].

A molecular view of the model Ac-NVal7-NMe2 after

1ns simulation in water (with starting geometry having

Φ, Ψ values of ~ 0, 90˚ and ~ 0, - 90˚ ) is shown in Fig-

ure 4. It is apparent from the results in Table 4 and the

molecular graphics shown in Figures 4 & 5; that the

interactions of water molecules with the carbonyl oxy-

gen of the backbone lead to the population of structures

with average Φ, Ψ values around -60, 145˚ and 60, -145˚.

The conformation with Φ, Ψ values of ~ -60, 145˚ is

called collagen type structure [66] and the structure with

inverse Φ, Ψ values of collagen type structure i.e. 60,

-145˚ is named as inverse-collagen type structure. Col-

lagen type structures are also well documented in globu-

lar proteins [67,41]. The distance between the carbonyl

oxygen of the peptoid backbone and hydrogen atoms of

water molecules are found to lie between 1.5 to 1.9 Å.

The angle/OHO(C) are observed to lie in the range from

150 to 180˚. This observation is consistent with the ex-

perimental finding that the hydrogen bond angle in bio-

logical systems is never 180˚ but less [68]. In QM cal-

culations both collagen and inverse-collagen type struc-

tures are predicted to be higher in energy (Table 4).

Helical structures with Φ = ± 79.2˚, Ψ = ± 174.6˚ with

F. S. Nandel et al. / Journal of Biophys ical Chemistry 2 (2011) 37-48

Table 4. Torsion angles for the peptoids in trans amide bond geometry after 1ns simulation with different starting geometries having

1) Φ, Ψ values of ~ 0˚, - 90˚and 2) Φ, Ψ values of ~ 0˚, 90˚.

Φ ψ ω χi, χj (deg) Φ ψ ω χi, χj (deg)

Ac-NAla7-NMe2 Ac-NVal7-NMe2

1 72.3 –159.2 178.2

1 56.3

﹣131.9–163.0 108.1

107.7 –153.3 175.2

61.0

﹣143.0–170.8 121.6

70.5 –113.8 157.7

79.6

﹣137.7 158.4 138.0

55.9 –120.1 175.3

63.4

﹣122.6–174.7 126.7

57.7 –128.4 177.2

64.9

﹣125.6 177.1 122.3

92.4 –137.1 159.9

77.5

﹣151.2–175.1 122.7

72.9 –138.5 179.3

–61.4 99.0 –172.5 113.3

2 –63.8 148.8 –162.6

2 –49.7 113.9 178.3 –104.2

–79.4 134.9 –174.4

–59.4 127.7 –174.0 –118.8

–117.7 148.1 –173.6

–66.4 153.8 166.6 –123.4

–83.5 –146.0 163.5

–58.5 128.7 168.8 –116.0

–90.5 –164.7 163.8

–75.4 125.9 –179.3 –120.9

–104.3 –156.7 160.2

–44.9 124.1 –171.8 –121.4

70.4 –117.5 157.2

–76.1 145.4 175.1 –104.6

Ac-NLeu7-NMe2 Ac-NIle7-NMe2

1 79.8 166.6 –169.6 95.5, –88.4

1 65.3 –154.6

–176.1 103.6, 69.4

46.8 –117.7 –176.2 –90.5, 148.2

57.8 –127.4

–162.7 112.6, 71.6

65.6 –162.9 –165.7 –145.6, –157.4

78.6 –155.4

–175.3 103.0, 110.6

81.1 –107.2 168.0 105.1, –79.0

64.3 –142.8

–189.6 124.8, 87.6

61.4 –108.2 179.6 –110.7, –162.9

65.9 –135.4 177.8 97.3, 87.4

55.3 –136.2 172.4 –97.3, 78.7

89.4 169.3

–168.7 102.9, 143.5

94.1 –152.8 163.2 131.6, –84.2

66.8 –120.6

–175.0 108.0, 76.5

2 –68.2 133.9 –170.5 113.5, –62.1

2 –87.8 –169.7 167.9 109.8, 87.9

–67.9 145.6 179.5 118.1, –83.6

–61.6 110.4 177.6 131.1, 152.9

–57.3 123.4 –176.0 119.7, –85.9

–75.1 146.8 –176.1 85.9, 153.6

–72.4 129.6 –160.9 85.1, –117.3

–61.8 152.9 174.1 123.7, –174.6

–64.6 142.5 –170.3 107.9, –70.7

–64.5 145.7 174.3 109.4, 95.6

–76.3 157.2 179.4 –118.9, –98.8

–50.8 135.3 –174.1 110.6, 76.9

–52.5 152.8 –174.9 115.5, –84.1

–67.0 137.1 176.5 104.9, 95.7

Table 5. Torsion angles for the model Ac-NVal7-NMe2 at different simulation time in water with starting conformation of Φ, Ψ, ω ~

0˚, -90˚, 180˚.

Φ, Ψ

Residue number →

Time/ ps

↓ 1 2 3 4 5 6 7

0.5 57.7, –149.1 68.8, –134.7 23.2, –88.7 12.8, –100.5 36.6, –112.7 17.4, –110.4 –20.9, –67.1

1.0 70.0, –152.6 62.5, –141.5 53.5, –128.9 43.2, –103.7 20.2, –96.2 68.4, –134.6 –27.7, –70.9

5.0 51.6, –137.2 70.8, 178.9 67.6, –125.4 66.5, –119.5 37.3, –100.6 62.9, –126.4 –30.2, –73.7

10.0 49.9, –123.8 73.2, 178.0 63.1, –140.2 46.8, –120.1 48.1, –133.7 67.0, –129.7 18.7, –100.6

1000.0 58.3, –131.9 61.0, –143.0 79.6, –137.7 63.4, –122.6 64.9, –125.6 77.5, –151.2 –61.4, 99.0

trans amide bond geometry for sarcosine have also been

reported by ab initio calculations using dielectric con-

stants to replicate an aqueous environment [69] but not

in explicit solvent. Our results are also consistent with

the peptoid backbone conformational landscape de-

scribed by Butterfoss et al. using ab initio Gaussian03

package [29].

Opening of Helical Structure without hydrogen

bonds: To gain insight into the opening of the helical

structures, whether opening starts from the N or C-terminal

F. S. Nandel et al. / Journal of Biophys ical Chemistry 2 (2011) 37-48

(a)

(b)

Figure 4. Molecular view of the (a) Collagen and (b) in-

verse-collagen type structures observed in the model

‘Ac-NVal7-NMe2’ after 1ns simulation in water with starting

geometry having Φ, Ψ values of ~ 0, 90˚and 0, -90˚ respec-

tively. As evident, such structures are stabilized by the interac-

tions of water molecules with carbonyl moieties of the peptoid

backbone. For clarity purposes, water molecules within 3 Å of

the peptoid surface are shown.

a pictorial view of the peptoid Ac-(NVal)7-NMe2 at dif-

ferent simulation times with water molecules within 3 Å

of the peptoid surface is shown in Figure 6. It is appar-

ent from the graphics that the opening of the helical

structure into the collagen or inverse-collagen type

structure begins at the N-terminal due to initial interac-

tions of water molecules with the acetyl carbonyl oxygen

that lead to the change of torsion angles. Analysis of the

simulation results at different time intervals given in

Table 5 reveal that opening of the helical structure with-

out hydrogen bonds takes place at the sub picoseconds

time scale. The number of hydrogen bonds formed be-

tween water molecules and the carbonyl moieties attain

the maximum val ues within 10 ps and thereafter remain

Figure 5. Plot of total energy (E) as a function of simula-

tion time for the model Ac-(NIle)7-NMe2 (black) and

Ac-(NLeu)7-NMe2 (red) for the collagen type conforma-

tions.

(

)

(

)

(b)

Figure 6. Snapshots of the peptoid ‘Ac-(NVal)7-NMe2’ at dif-

ferent simulation intervals (a) 1ps, (b) 5ps and (c) 10ps with

water molecules within 3 Å of the peptoid surface indicates

that the opening of the helical structure without hydrogen

bonds starts at the N-terminal.

constant throughout the simulation period (Figure 7).

6. CONCLUSIONS

Aliphatic polypeptoid models adopt degenerate helical

structures without hydrogen bonds with Φ, Ψ values of ~

0,  90˚ in trans amide bond geometry that are stabilized

(a)

(b)

Figure 7. Number of hydrogen bonds formed between car-

bonyl groups of the backbone and water molecules for the

model ‘Ac-(NVal)7-NMe2’ (a) increases within first 10 ps and

thereafter, (b) remains constant on simulation in water.

F. S. Nandel et al. / Journal of Biophys ical Chemistry 2 (2011) 37-48

by carbonyl interactions. The population of poly-NLeu

in only one state with Φ, Ψ values of ~ 0, 90˚ is attrib-

uted to the difference in the side chain branching pat-

terns of these residues. A single handed template was

realized by incorporating L-leu or L-val at the C-termi-

nal of poly-NIle sequences. Such templates provide pat-

terns and find utility in generating a comple- mentary

molecule. In peptoids, helical structures without hydro-

gen bonds can also be exploited for the design of surfac-

tant molecules by incorporating charged residues at the

terminal positions. Simulation studies reveal that inter-

actions of water molecules with the carbonyl moieties of

peptoid backbone act as the primary driving force behind

the opening of helical structures without hydrogen bonds

resulting in the population of collagen or in-

verse-collagen type structures.

7. ACKNOWLEDGMENTS

We gratefully acknowledge the funding for this project by the De-

partment of Biotechnology, India.

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