Journal of Molecular Structure: THEOCHEM 901 (2009) 81–87

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Journal of Molecular Structure: THEOCHEM

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Effects of side chains in gas-phase amino acids: Conformationalanalysis and relative stabilities

Gang Yang a,b,*, Lijun Zhou a, Yuangang Zu a, Yujie Fu a, Rongxiu Zhu b, Chengbu Liu b,*

a Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University, 26 Hexing Road, Harbin 150040, PR Chinab Institute of Theoretical Chemistry, Shandong University, Jinan 250100, PR China

a r t i c l e i n f o

Article history:Received 16 October 2008Received in revised form 6 January 2009Accepted 6 January 2009Available online 13 January 2009

Keywords:Density functional calculationsConformational analysisHydrogen bondsRelative stabilitySide chains

0166-1280/$ - see front matter � 2009 Elsevier B.V. Adoi:10.1016/j.theochem.2009.01.006

* Corresponding authors. Tel.: +86 0451 82192223;Yang).

E-mail addresses: theobiochem@gmail.com (G. Yan

a b s t r a c t

B3LYP and MP2 theoretical methods were employed to study the structures and relative stabilities of theGly, Ala, Val, Aib, F-Gly, I-Gly and dF-Gly conformers. It was found that the relative stabilities of the Gly,Ala, Val and Aib conformers increase in the same orders of V < IV < III < II < I, due to the similar shapes ofthe corresponding conformers. Two exceptions exist for the above orders: In Gly, conformer IV is slightlymore stable than conformer III; in Aib, conformer II is more stable than conformer I. The relative stabilityof conformer II vs. I is gradually enhanced by the substitutions of the lateral H atoms with the alkylgroups, especially in the case of the double substitutions to form Aib. The geometries and relative stabil-ities of the F-Gly, I-Gly and dF-Gly conformers are quite different from Gly as well as Ala, Aib and Val withthe alkyl side chains. The driving forces in the conformers of the halogenated amino acids are mainly theintramolecular hydrogen bonding interactions, at least four hydrogen bonds formed in each dF-Gly con-former. For F-Gly and I-Gly, three conformers II–IV exist whereas conformers I and V are spontaneouslytransformed into conformers IV and III, respectively. It was found that the functional rather than alkylside chains interact strongly with the NH2CHCOOH fragments and accordingly have more remarkableinfluences on the geometries and relative stabilities of the conformers.

� 2009 Elsevier B.V. All rights reserved.

1. Introduction

In crystalline state and aqueous solutions, amino acids exist in thezwitterionic forms [1–3]. In gas phase, however, amino acids are pre-dominated by the canonical isomers. The zwitterions of the gas-phase amino acids are not local energy minima, even for argininewith the extremely basic guanidine group [4–9]. Glycine has beenwidely used as computational models of proteins and many at-tempts were made to stabilize the glycine zwitterions [3,6,7,10–18].

Besides the stabilization of amino acid zwitterions, the confor-mational studies of gas-phase amino acids are also a recent re-search focus [4,19–26]. As the landmark contributions of Császárindicated [3,19], eight conformers exist on the potential energysurface (PES) of the gas-phase glycine molecule. The five top pop-ulated conformers of glycine were shown in Fig. 1 (R1 = R2 = H)[4,13,27]. It is generally believed that conformer I is stabilized bythe two intramolecular N–H hydrogen bonds; however, Wanget al. [28] insisted that the superior stability of this conformershould be due to the hyperconjugation. As to alanine (R1 = CH3,R2 = H, see Fig. 1), the rotational and quartic centrifugal distortionconstants of its two conformers were determined with the micro-wave and millimeter wave spectra [29]. Using theoretical calcula-

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fax: +86 0451 82102082 (G.

g), cbliu@sdu.edu.cn (C. Liu).

tions, Gao et al. [30] and Császár [21] obtained thirteen conformersfor the gas-phase alanine molecule. The relative energies indicatedthat five of them have observable populations, corresponding ex-actly to the conformers of glycine. Note that only the natural L-va-line was counted here. Owing to the presence of the lateralisopropyl group, the conformational behavior of valine becomesmore complicated (R1 = CH(CH3)2, R2 = H, see Fig. 1). Three moststable valine conformers were provided by Lesarri et al. [22], usinglaser-ablation molecular-beam Fourier transform microwave (LA-MB-FTMV) technique and ab initio calculations.

As is well-known, the side chains of amino acid residues in pro-teins are of special importance to the formation and maintenanceof the three-dimensional (3D) structures [31–33]. In this work, theeffects of side chains were discussed on the basis of the conforma-tional studies of seven amino acids. Apart from glycine, alanineand valine described above, another four amino acids were consid-ered; i.e., Aib, F-Gly, I-Gly and dF-Gly (Fig. 1). 2-Aminoisobutyric acid(Aib, R1 = R2 = CH3) is a non-protein amino acid; however, it plays animportant role in the transports of cultured McCoy cells and confor-mational transformations of peptides and proteins [34,35]. Theother three are halogenated amino acids: F-Gly (R1 = F, R2 = H), I-Gly (R1 = I, R2 = H) and dF-Gly (R1 = R2 = F). The introduction of thehalogen elements into the biologically active molecules bring aboutprofound changes in the physical, chemical and biological proper-ties, and therefore their synthesis has recently received much atten-

Fig. 1. Five conformers of the amino acids presently studied.

82 G. Yang et al. / Journal of Molecular Structure: THEOCHEM 901 (2009) 81–87

tion [36,37]. The conformational behaviors of Aib, F-Gly, I-Gly anddF-Gly were explored for the first time. On such basis, the effectsof side chains in amino acids were discussed.

2. Computational details

All the calculations were performed with Gaussian 03 softwarepackage [38]. The Becke 3-parameter Lee-Yang-Parr exchange-cor-relation (B3LYP) functional [39,40] was testified by numerous liter-atures [20,28,41–48] to be suitable to treat the amino acid relatedsystems. The standard 6-311++G(d,p) basis set was used for all theelements except I. Owing to the significant relativistic effects, theinner electrons of the I element were treated with LanL2DZ effec-tive core potentials (ECP) and the valence electrons with LanL2DZbasis set [49]. The NBO charge analysis was accomplished at thesame level of theory [50].

As suggested by the referee, the single-point energies of all thestructures were evaluated at MP2/Aug-CC-pVDZ level of theory,using the B3LYP/6-311++G(d,p) geometries. In addition, the con-formers of Gly, Ala, Aib and F-Gly were also optimized with theMP2/Aug-CC-pVDZ method. It indicated that the MP2/Aug-CC-pVDZ geometries and energies are in excellent agreements withthose of B3LYP/6-311++G(d,p) and MP2/Aug-CC-pVDZ//B3LYP/6-311++G(d,p) levels, respectively. Accordingly, the geometric andenergetic analysis of this work was based on the latter two theoret-ical levels, except specially pointed out.

3. Results and discussion

The experimental and computational results [4,13,20–22,25,27]indicated that amino acids such as Gly, Ala, Pro and Val are pre-dominated by not more than five conformers. Accordingly, the five

top populated conformers of amino acids in Fig. 1 were consideredin this work. The present geometries and relative energies of Gly,Ala and Val are in excellent agreements with the previous data[4,13,20–23,28].

For the different conformers of amino acids, the direct bond dis-tances are changed within a narrow range and the standard devia-tions are quite small [4,13,20,21–23,28,51]. Take C3–O5 bonds forexample. The C3–O5 bond distances of all the presently studiedconformers fall within 1.340–1.362 ÅA

0

, with the exception of the va-lue 1.333 ÅA

0

in conformer IV(dF-Gly). The best structural parametersto characterize and distinguish different conformers should be thedihedrals. For all the conformers of the seven amino acids in Fig. 1,the four atoms in the carboxyl groups (C3O5O4H6, see Fig. 1) re-main nearly planar. Their deviations from planar are usually lessthan 2.0�, and in some conformers such as I(Gly), III(Gly), IIA(Val)and I(Aib), the deviations are even below 0.1�. However, largerdeviations are observed in conformers II of some amino acids.The W(O5C3O4H6) dihedrals are equal to 176.34� in conformerIIB(Val), 175.53� in conformer II(F-Gly), �176.61� in conformerII(I-Gly) and 176.43� in conformer II(dF-Gly), respectively. Owingto the more deviations from planar, the conjugations in these car-boxyl groups are reduced by certain degrees. The structuralanalysis indicated that the W(O4C3C2N1), W(O4C3C2R2) andW(C3C2N1H7) dihedrals can finely characterize and distinguishthe various conformers of amino acids. The values of the threedihedrals were collected and listed in Table 1. If interested, pleasefind the complete geometric details in Supplementary materials.

3.1. Val

For Val, Lesarri et al. [22] provided the structures and relativeenergies of conformers I–III. Presently, conformers IV and V were

Table 1Three important dihedrals (in degrees) in amino acids.a

I II III IV V

W(O4C3C2N1)Gly �179.99 6.90 �2.77 162.22 36.31Ala 162.33 11.56 �45.56 154.02 45.52Val

A 164.41 10.89 �14.11 157.43 25.16B 132.49 20.25 �60.25 126.08 63.20C 147.90 6.08 �32.43 149.17 33.11

Aib 179.60 12.23 55.88 159.66 47.44F-Gly 31.69 �51.23 148.21I-Gly 16.06 �36.36 153.54dF-Gly �154.64 31.88 �64.09 154.89 47.63

W(O4C3C2R2)Gly 56.58 �114.01 �127.12 40.60 �89.58Ala 42.88 �103.23 �164.35 36.69 �75.12Val

A 45.70 �103.24 �132.75 40.79 �95.32B 13.68 �92.39 �177.19 10.67 �56.19C 29.39 �108.71 �150.48 32.72 �86.95

Aib 59.86 �104.98 �63.22 41.05 �74.98F-Gly �88.01 �174.53 22.91I-Gly �105.29 �167.65 20.15dF-Gly 81.61 �86.19 174.03 31.11 �77.28

W(C3C2N1H7)Gly 59.02 106.29 59.35 38.19 �59.28Ala 56.47 99.22 59.52 43.75 �57.09Val

A 43.31 97.61 51.37 42.84 �42.81B 50.06 88.10 56.25 60.04 �55.79C 47.17 103.66 54.19 42.86 �48.31

Aib 58.21 97.96 63.74 42.57 �62.26F-Gly 71.46 57.22 47.73I-Gly 79.23 47.96 39.39dF-Gly �39.35 73.79 52.78 39.28 �54.10

a R2 stands for H10 in Gly, Ala, Val, F-Gly, I-Gly or C10 in Aib or F10 in dF-Gly,respectively.

Fig. 3. The total energies of the fifteen configurations corresponding to the five Valconformers obtained at MP2/Aug-CC-pVDZ//B3LYP/6-311++G(d,p) level of theory.

G. Yang et al. / Journal of Molecular Structure: THEOCHEM 901 (2009) 81–87 83

taken into calculations as well. Owing to the staggered orientationsof the isopropyl group, altogether fifteen configurations were re-sulted in; i.e., three configurations correspond to each of the fiveconformers (Fig. 2). The W(O4C3C2N1), W(O4C3C2H10) andW(C3C2N1H7) dihedrals of the fifteen configurations were givenin Table 1. It was found that the staggered orientations of the lat-eral isopropyl groups produce inconsistent influences on the threeconfigurations of the different conformers. For example, theW(O4C3C2N1) dihedrals increase in the orders of 132.49� inIB < 147.90� in IC < 164.41� in IC, 6.08� in IIC < 10.89� inIIA < 20.25� in IIB, �60.25� in IIIB < �32.43� in IIIC < �14.11� in IIIA,126.08� in IVB < 149.17� in IVC < 157.43� in IVA and 25.16� inVA < 33.11� in VC < 63.20� in VB, respectively. It was caused by

Fig. 2. The schematic presentations of three configurations in conformer

the van der Waals (vdW) interactions between the isopropyl andNH2CHCOOH fragments. Among the five conformers, II is the mostrepresentative since it has the most comparable dihedral valueswith glycine (Table 1). The W(O4C3C2N1), W(O4C3C2H10) andW(C3C2N1H7) dihedrals of IIC(Val) are the closest to those of con-former II(Gly) in that the orientation of the isopropyl group pro-duces the least disturbance to the NH2CHCOOH fragments. InIIA(Val), the two isopropyl CH3 groups show strong vdW repulsionstowards the amido H atoms, which are however symmetric andbalanced. The situation is changed in IIB(Val), where their repul-sions to the two amido H atoms can not be balanced, causing theC2–N1 bond to rotate remarkably. As a result, the largest devia-tions from conformer II(Gly) were observed in IIB(Val) (Table 1).Along with the vdW repulsions, there are also vdW attractions be-tween the isopropyl and NH2CHCOOH fragments; e.g., in IA, twoN1–HSC distances were optimized at 2.714 and 2.743 ÅA

0

, one O4–HSC distance at 2.600 ÅA

0

, and one O5–HSC at 2.953 ÅA0

, respectively.Note that HSC indicated the H atoms are from the side chains (SC).

As shown in Fig. 3, the total energies of conformers I, IV and Vincrease in the same sequences as A < B < C whereas of conformerII as A < C < B and of conformer III as C < A < B, respectively. Theconfigurations of conformers I–III were previously reported by Les-arri et al. [22], where the sequences of energy changes are exactlythe same as ours. Configurations A are of the lowest energies for allthe conformers except III, where configuration B is the most stable.

I(Val) due to the different orientations of the isopropyl side chains.

84 G. Yang et al. / Journal of Molecular Structure: THEOCHEM 901 (2009) 81–87

As described above, the lateral isopropyl groups form vdW repul-sive and attractive interactions with the NH2CHCOOH fragments.Among the three configurations of conformer III, the isopropylgroup in configuration B has the least vdW repulsions with theamido H atoms as evidenced by the large HSC–H7 distances. Theshortest HSC–H7 distances are equal to 2.378 ÅA

0

in IIIA, 2.536 ÅA0

inIIIB and 2.277 ÅA

0

in IIIB, respectively. In addition, two N1–HSC dis-tances in IIIB were optimized to be 2.598 and 2.666 ÅA

0

, indicatingstrong vdW attractions.

Each conformer of valine has three configurations due to thestaggered orientation of the isopropyl side chain. In order to com-pare the relative stabilities of the five valine conformers and eval-uate the effects of side chains in different amino acids, the energyof each valine conformer (EX, X = I, II, III, IV, V) was estimated bythe weighted value of the three configurations (EA, EB and EC, seeFig. 2 for the three configurations of conformer I for example).

PX ¼expð�DEXÞ=RT

PX expð�DEXÞ=RT

ð1Þ

EX ¼ EA � PA þ EB � PB þ EC � PC ð2Þ

where EX and PX are the energy and population of configuration X(X = A, B, C). In each conformer, the lowest-energy configurationwas chosen to be the energy benchmark. R and T stand for gas con-stant and temperature, equal to 8.314 J mol�1 K�1 and 298.15 K(normal temperature), respectively.

Using Eqs. (1) and (2), the relative stabilities of the five Val con-formers were obtained, increasing in the order of V < IV < III < II < I.It is exactly identical to the order of the Ala conformers. The onlydifference with Gly is the sequence of conformers III and IV, theformer being slightly more stable in Ala and Val whereas on thecontrary in Gly (Table 2). As a matter of fact, conformers III andIV in each of these three amino acids have very close total energiesand therefore their relative stabilities are very sensitive to the the-oretical levels. From Table 2 it was found that the present resultsare in good agreement with those of the MP2/Aug-CC-pVDZ meth-od, also given in Table 2 (in parentheses).

3.2. Aib

Conformer I(Gly) belongs to the Cs point group, and by replac-ing R1 = H with CH3, it is evolved into conformer I(Ala), character-istic of the C1 point group. However, the Cs point group isrestored by the further replacement of R2 = H with CH3, formingconformer I(Aib). According to the point groups, the NH2CHCOOHgeometry of conformer I(Aib) rather than I(Ala) should resemblethat of conformer I(Gly), which was confirmed by the presentoptimization results. For example, the W(O4C3C2N1) dihedralsequal �179.99� in Gly, 162.33� in Ala and 179.60� in Aib, respec-tively (Table 1). That is, the effects of the two lateral CH3 groups

Table 2The single-point energies (in kJ mol�1) of the amino acid conformers obtained at MP2/Aug-CC-pVDZ//B3LYP/6-311++G(d,p) level of theory.a

Gly Ala Val Aib F-Gly I-Gly 2F-Gly

I 0.00 0.00 0.00 1.63 0.00(0.00) (0.00) (1.63)

II 2.13 1.56 0.77 0.00 13.87 4.51 15.06(2.34) (1.81) (0.00) (13.84)

III 6.65 4.53 4.17 4.46 2.03 4.68 14.59(6.66) (4.53) (4.53) (1.91)

IV 5.15 4.73 5.41 7.33 0.00 0.00 0.01(5.21) (4.79) (7.30) (0.00)

V 10.16 7.45 10.46 8.40 3.95(10.15) (7.56) (8.47)

a The relative energies in parentheses were obtained on the MP2/Aug-CC-pVDZgeometries.

in I(Aib) are perfectly cancelled out, causing its structural resem-blance with I(Gly). The other conformers (II–V) of Gly, Ala andAib are all characteristic of the C1 point group, and the geometriesof Ala rather than Aib are in better agreements with Gly. Con-former IV is an exception, where the geometries of Aib are in bet-ter agreements with Gly. It indicated that the effects of the twolateral CH3 groups in Aib can not be cancelled out in these con-formers and therefore cause the larger structural deviations fromGly than Ala. Nevertheless, all the corresponding conformers ofGly, Ala, Aib and Val have similar shapes, see the details in Sup-plementary materials.

The relative stabilities of the Aib conformers increase in the or-der V < IV < III < I < II, which is close to those of the above Gly, Alaand Val (Table 2). The largest inconsistency of Aib with Gly, Ala andVal is the exceptionally high stability of conformer II. As Table 2indicated, the energy differences between the two most concernedconformers I and II were calculated to be �1.63 kJ mol�1 for Aib<0.77 kJ mol�1 for Val <1.56 kJ mol�1 for Ala <2.13 kJ mol�1 forGly, respectively. Compared with Gly, the relative stability of con-former II vs. I in Ala is improved somewhat by the substitution ofR1 = H with CH3. With the bulky R1 = CH(CH3)2 group in Val, therelative stability is further improved. In Gly, the intramolecularhydrogen bonds play a crucial role in the conformational prefer-ence of I over II, especially the two O–H hydrogen bonds[4,19,20]. The alkyl side chains in I(Ala) and II(Val) severely weak-en the O5–H8 hydrogen bonds although at the same time strength-en somewhat the O5–H7 hydrogen bonds (Table 3). Comparedwith II(Gly), The intramolecular N1-H6 hydrogen bonds in II(Ala)and II(Val) are observed to have been reinforced, which greatly im-proves the relative stability of conformer II. The exceptionally highstability of conformer II in Aib is tentatively explained by thefavourable substitution of the lateral H atoms in Gly with the alkylgroups. Eqs. (3) and (4) below indicated that the substitution ofR1 = H with CH3 in Gly to form Ala improves the relative stabilityof conformer II vs. I.

DEXðAla-GlyÞ ¼ EXðAlaÞ � EXðGlyÞ: ð3Þ

where DEX(Ala-Gly) is the energy difference between the corre-sponding conformers of Gly and Ala (X = I, II).

DDEðAla-GlyÞ ¼ DEIIðAla-GlyÞ � DEIðAla-GlyÞ ð4Þ

DDE(Ala-Gly) was calculated to be �0.57 kJ mol�1. It indicated thatthe replacement of the first lateral H atom with CH3 favours slightlyconformer II vs. I. The identical situation can also be found in Valwhere R1 = CH(CH3)2.

In the same way, the energy difference due to the furtherreplacement of R2 = H with CH3 to form Aib can be obtained:

DEXðAib-AlaÞ ¼ EXðAibÞ � EXðAlaÞ ð5ÞDDEðAib-AlaÞ ¼ DEIIðAib-AlaÞ � DEIðAib-AlaÞ ð6Þ

DDE(Ala-Aib) was calculated to be �3.76 kJ mol�1, much largerthan the DDE(Ala-Gly) value. Accordingly, the relative stability ofconformer II vs. I is gradually enhanced by the substitutions of

Table 3The hydrogen-bond distances (in ÅA

0

) in conformers I and II of Gly, Ala, Val and Aib.

I II

O5–H7 O5–H8 O5–H6 N1–H6

Gly 2.841 2.841 2.305 1.934Ala 2.689 2.933 2.297 1.902ValA 2.529 3.059 2.293 1.896B 2.612 3.230 2.293 1.881C 2.556 3.125 2.289 1.870Aib 2.718 2.728 2.283 1.879

G. Yang et al. / Journal of Molecular Structure: THEOCHEM 901 (2009) 81–87 85

the lateral H atoms with the alkyl groups, especially in the case ofthe second substitution to form Aib.

3.3. F-Gly and I-Gly

As to the gas-phase fluorinated Gly molecule (F-Gly), there ex-ist three independent conformers; i.e., II–IV. The geometry opti-mizations witnessed the spontaneous transformations ofconformer I to IV and conformer V to III, which were driven bythe formations of more intramolecular hydrogen bonds [4,20,51]. The W(C3C2N1H7) dihedrals in conformers II(Gly) and II(F-Gly) were optimized to be 106.29� and 71.46�, respectively, indi-cating the obvious rotation of the C2–N1 bond in conformer II(F-Gly) compared with conformer II(Gly). As a result, two intra-molecular hydrogen bonds will be formed between the F9 andthe adjacent H atoms (Fig. 4). The F9–H7 and F9–H8 distancesare equal to 2.562 and 2.717 ÅA

0

, respectively. The C2–N1 rotationsare also observed in conformers III(F-Gly) and IV(F-Gly), with fourintramolecular hydrogen bonds formed in each conformer, seethe details in Fig. 4.

Conformer IV(F-Gly) was calculated to have the lowest energy(Table 2), and III(F-Gly) is slightly more unstable with the energydifference of 2.03 kJ mol�1. These two conformers are highly stabi-lized by the presence of four strong intramolecular hydrogenbonds. Owing to the presence of one fewer hydrogen bond, con-former II(F-Gly) is 13.87 kJ mol�1 higher in energy than conformerIV(F-Gly). Table 2 indicated that the relative stabilities of the F-Glyconformers increase in the order II < III < IV.

The conformational behavior of I-Gly quite resembles that of F-Gly. Three conformers II–IV exist and conformers I and V are spon-taneously transformed into IV and III, respectively. However, theaffinity of the I element towards the H atoms is much weaker thanthat of the F element, and therefore the conformational deviationsof I-Gly from Gly are generally smaller than those of F-Gly (Table1). Besides the I9–H7 and I9–H8 hydrogen-bonded pairs, anothertwo hydrogen bonds exist in conformers III(I-Gly) and IV(I-Gly)whereas one in conformer II(I-Gly). The NBO charges of the I9atoms were calculated to be 0.079 |e| in conformer II(I-Gly),�0.099 |e| in conformer III(I-Gly) and �0.110 |e| in conformerIV(I-Gly), respectively. Accordingly, the I9 atom in conformer II(I-Gly) shows attractive interactions with the amido groups, contraryto the situations in conformers III(I-Gly) and IV(I-Gly). It greatly re-duces the energy of conformer II(I-Gly) and improves its relativestability. The relative stabilities of the I-Gly conformers increasein the order III < II < IV (Table 2). Conformers II(I-Gly) and III(I-Gly) are of very close energies although the numbers of hydrogenbonds are equal to three and four in the former and latter conform-ers, respectively. The inconsistencies of the relative stabilities ofthe F-Gly and I-Gly conformers (Table 2) are caused by the im-

Fig. 4. Conforme

proved stability of conformer II(I-Gly) due to the attractive interac-tions between the I9 and amido groups. The relative stabilities ofthe F-Gly conformers are predominated by the intramolecularhydrogen bonds.

3.4. dF-Gly

As shown in Figs. 1 and 5, the double fluorine substitutions ofR1 = R2 = H in Gly cause the formation of dF-Gly, whose conforma-tional behavior distinguishes remarkably from both Gly and F-Gly(Table 1). The W(C3C2N1H7) dihedrals in conformers I(Gly), IV(F-Gly) and I(dF-Gly) were calculated to be 59.02�, 47.73� and�39.35�, respectively. Here the value of conformer IV(F-Gly) wasused for conformer I(F-Gly) owing to the spontaneous transforma-tion of conformer I(F-Gly) into IV(F-Gly). In conformer I(F-Gly), theanti-clockwise rotation of the C2–N1 bond causes the formation ofF9–H7 and F9–H8 hydrogen bonds, thus forming conformer IV(F-Gly); or else, only a single hydrogen bond of F9–H7 would beformed. However, the double fluorine substitutions in dF-Gly en-sure the formation of three F–H hydrogen bonds in conformer Iwhether the C2–N1 bond rotates anti-clockwise or clockwise,which is confirmed by the striking structural similarities betweenconformers I and IV (Fig. 5). Conformer I(dF-Gly) is formed bythe clockwise rotation of the C2–N1 bond, and if by the anti-clock-wise rotation, it would be transformed into conformer IV(dF-Gly)just as in F-Gly (Fig. 4). The double fluorine substitutions stabilizesconformer V(dF-Gly), where five intramolecular hydrogen bondsare formed (Fig. 5). Accordingly, conformer V(dF-Gly) will not bespontaneously transformed into conformer III(dF-Gly), either. In-stead, conformer III(dF-Gly) with four intramolecular hydrogenbonds is found to be less stable than conformer V(dF-Gly) (Table2). As to conformer II(dF-Gly), its structure is quite similar to thatof conformer II(F-Gly), which can be observed from the dihedralvalues in Table 1: Both of their W(O4C3C2N1) dihedrals areapproximated at 31.8� and the deviation of either W(O4C3C2H10)or W(C3C2N1H7) dihedrals is less than 2.5�. Owing to the strongattractions by the F9 and F10 atoms towards the amido H7 andH8 atoms, the N1–H6 distance in conformer II(dF-Gly) is enlargedto 2.125 ÅA

0

instead of 2.089 ÅA0

in conformer II(F-Gly) and 1.934 ÅA0

inconformer II(Gly).

The relative stabilities of the dF-Gly conformers increase in theorder II < III < V < IV < I (Table 2). The order of conformers II–IV isidentical to that of F-Gly. However, the energy difference betweenconformers IV(dF-Gly) and III(dF-Gly) is 14.58 kJ mol�1, much lar-ger than the corresponding values of 2.03 and 4.68 kJ mol�1 in F-Gly and I-Gly, respectively. It was caused by the different numbersof hydrogen bonds: Four and five are formed in conformers III(dF-Gly) and IV(dF-Gly), respectively (Fig. 5).

rs of F-Gly.

Fig. 5. Conformers of dF-Gly.

86 G. Yang et al. / Journal of Molecular Structure: THEOCHEM 901 (2009) 81–87

From the above discussions, it was found that the relative sta-bilities of the halogenated Gly conformers have quite different or-ders from those of Gly, Ala, Val and Aib (Table 2). The lateral alkylgroups of the amino acids produce slight influences on the relativestabilities. However, the functional groups that interact stronglywith the NH2CHCOOH fragments will have remarkable influenceson the geometries and further on the relative stabilities of the stud-ied conformers [51]. As to the present F and I functional groups, thesingle substitutions transform spontaneously one conformer to an-other and causes conformer IV to be the most stable. In all the hal-ogenated Gly molecules (F-Gly, I-Gly and dF-Gly), conformer II isvery unstable, quite different from the situations of Gly and theother amino acids with alkyl side chains (Table 2). In addition,the double fluorinations of Gly to form dF-Gly stabilize conformersI and V, especially V, which do not exist in the single halogenatedamino acids such as F-Gly and I-Gly. The driving forces of the con-formational stabilities in the halogenated amino acids (F-Gly, I-Glyand dF-Gly) are mainly the intramolecular hydrogen bondinginteractions, and therefore the formation of more intramolecularhydrogen bonds tends to stabilize the conformers.

4. Conclusions

The structures and relative stabilities of the Gly, Ala, Val, Aib, F-Gly, I-Gly and dF-Gly conformers were explored with B3LYP andMP2 theoretical methods. On such basis, the effects of side chainsin amino acids were discussed, with the main conclusions givenbelow.

The present geometries and relative energies of Gly, Ala and Valare in good agreement with the previous data. For the different Valconformers, the lateral isopropyl groups exert inconsistent struc-tural influences to the three configurations, which can be elucidatedby the repulsive and attractive vdW interactions between the sidechains and amido groups. As a result, the relative stabilities of thethree configurations change in the different orders for the five Val

conformers (Fig. 3). Owing to the balancing effects of the two lateralCH3 groups, conformer I(Aib) rather than conformer I(Ala) has moreclose geometry to conformer I(Gly). The geometric resemblances ofthe corresponding Gly, Ala and Aib conformers can generally eluci-dated with the aid of point groups, see the details in text.

The relative stabilities of the Gly, Ala, Val and Aib conformersincrease in the same orders of V < IV < III < II < I, which are dueto the similar shapes of the corresponding conformers. There aretwo exceptions to the above orders: In Gly, conformer IV is morestable than conformer III; in Aib, conformer II is more stable thanconformer I. The energy differences of the two most concernedconformers I and II were further studied, and it was found thatthe relative stability of conformer II vs. I is gradually enhancedby the substitutions of the lateral H atoms with the alkyl groups,especially in the case of the double substitutions to form Aib.

The conformational behaviors of F-Gly and I-Gly quite resembleeach other. Three conformers II–IV exist whereas conformers I andV are spontaneously transformed into IV and III, respectively. Ow-ing to the driving forces of forming more intramolecular hydrogenbonds, the conformers of F-Gly and I-Gly, especially F-Gly with theF elements having higher proton affinities, deviate greatly fromthose of Gly, Ala, Aib and Val. The relative stabilities of the F-Glyconformers increase in order II < III < IV. The relative stabilities ofthe I-Gly conformers differ from this order in that conformer II(I-Gly) is stabilized over III(I-Gly) due to the attractive interactionsbetween the I9 and amido groups.

The further fluorination of the R2 = H atom in F-Gly to form dF-Gly restores conformers I and V. The conformational behavior ofdF-Gly distinguishes remarkably from both Gly and F-Gly, see thedetails in the text. The dF-Gly conformers are highly stabilized bythe numerous intramolecular hydrogen bonds, five in conformersI, IV, V and four in conformers II, III. The relative stabilities ofthe dF-Gly conformers increase in order II < III < V < IV < I, withthe relative stabilities of conformers II–IV changing in the same or-der of F-Gly.

G. Yang et al. / Journal of Molecular Structure: THEOCHEM 901 (2009) 81–87 87

The relative stabilities of the conformers in the halogenatedamino acids (F-Gly, I-Gly and dF-Gly) are quite different from thoseof Gly or other amino acids with the alkyl side chains (Ala, Aib andVal). Compared with the alkyl side chains in Ala, Val and Aib, thefunctional side chains such as F and I in F-Gly, I-Gly and dF-Glyproduce much more obvious influences on the geometries and rel-ative stabilities of the conformers. The driving forces of the confor-mational stabilities in the halogenated amino acids are mainly theintramolecular hydrogen bonding interactions, and the formationof more intramolecular hydrogen bonds tends to stabilize theconformers.

Acknowledgements

This work was financially supported by the Major State BasicResearch Development Programs (No. 2004CB719902), NationalNatural Science Foundation (No. 20633060) and the TalentedFunds of Northeast Forestry University (No. 220-602042).

Appendix A. Supplementary data

Supplementary data associated with this article can be found, inthe online version, at doi:10.1016/j.theochem.2009.01.006.

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