Does the Residues Chirality Modify the Conformation of a Cyclo

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Does the Residues Chirality Modify the Conformation of a Cyclo-Dipeptide? Vibrational Spectroscopy of Protonated Cyclo Diphenylalanine in the Gas Phase Ivan Alata, Ariel Francis Pérez-Mellor, Feriel Ben Nasr, Debora Scuderi, Vincent Steinmetz, Fabrice Gobert, Nejmeddine Jaïdane, and Anne Zehnacker-Rentien J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.7b06159 • Publication Date (Web): 05 Sep 2017 Downloaded from http://pubs.acs.org on September 14, 2017

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The Journal of Physical Chemistry

Does the Residues Chirality Modify the Conformation of a Cyclo-Dipeptide? Vibrational Spectroscopy of Protonated Cyclo Diphenylalanine in the Gas Phase Ivan Alata1, Ariel Pérez-Mellor1, Feriel Ben Nasr1,2, Debora Scuderi3, Vincent Steinmetz3, Fabrice Gobert3, Nejm-Eddine Jaïdane2, Anne Zehnacker-Rentien1*. 1

Institut des Sciences Moléculaires d’Orsay (ISMO), CNRS, Univ. Paris-Sud, Université Paris-Saclay, F-91405 Orsay, France 2

Laboratoire de Spectroscopie Atomique Moléculaire et Applications (LSAMA) Université de Tunis El Manar, Tunis 1060, Tunisia

3

CNRS, Laboratoire de Chimie Physique (LCP), UMR8000, Orsay, F-91405 and Univ. Paris-Sud, Orsay, F-91405, France

Abstract

The structure of a protonated diketopiperazine dipeptide, cyclo diphenylalanine, is studied by means of Infra-Red Multiple Photon Dissociation (IRMPD) spectroscopy combined with quantum chemical calculations. Protonation exclusively occurs on the oxygen site and, in the most stable conformer, results to an intramolecular OH…π interaction, accompanied by a CH…π interaction. Higher-energy conformers with free OH and NH…π interactions are observed as well, due to kinetic trapping. Optimization of the intramolecular interactions involving the aromatic ring dictates the geometry of the benzyl substituents. Changing the chirality of one of the residue has consequences on the CH…π interaction, which is of CαH…π nature for LD while LL shows a CβH…π interaction. Higher-energy conformers also display some differences in the nature of the intramolecular interactions.

*e-mail : [email protected]

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1. Introduction Chirality is one of the most striking characteristics of life and is ubiquitous in the chemistry of living organisms.1 The homochirality of life has been suggested to happen through initial symmetry breaking, followed by propagation and amplification,2 possibly by autocatalysis.3 It manifests itself by the incorporation of molecules of a specific chirality throughout life-related biological reactions. It is significant however that once the biological processes has stopped, homochirality tends to vanish. Amino acids racemization has indeed been observed in Pleistocene cave bear dentine and is used as a dating method.4 Chirality and stereochemistry play an important role in various biochemical reactions such as protein folding or enzymatic catalysis.1,5,6 Exogenous molecules like drugs also act differently depending on the chirality of their stereogenic centers.7 Numerous artificial drugs must therefore be of a specific chirality to be integrated into the complex biological system of living organisms. The different involvement of two enantiomers or diastereomers in biological reactions rests upon several factors, some of them being related to the environment or the solvent, others being intrinsic to the molecule itself. Gas phase studies enable studying the structural differences between diastereomers without the perturbations caused by the solvent.8-19 Studying each diastereomer in isolated conditions allows understanding the influence of chirality on intra and intermolecular interactions, which in turn govern the enantioselectivity of the reactive processes. Many biological molecules are protonated in physiological conditions, which influences their chemical and physical properties as well as the chemical processes they are involved in. Protonation can, for example, serve as a trigger for reversible structural interconversion from extended to helical forms of pyridine-derived oligoamides.20 The structure of protonated polypeptide often differs strongly from that of neutral ones. In particular, protonated polyalanines in the gas phase contrast with neutral ones and fail to adopt a helical conformation because the location of the charge at the N-terminus destabilizes the helix.21 Chirality-induced structural changes have been studied in small protonated peptides in isolated conditions. Limited differences have been observed between protonated or neutral LL and LD diphenylalanines or tetraphenylalanine.22-24 However, cyclic species seem to show increased sensitivity to stereochemical factors because of the constraints related to the ring. The structure of protonated model systems like 1-amino-2-indanol 25 or 4-hydroxyproline diastereomers15 are indeed sensitive to chirality, as also are neutral cyclic systems.13,16 This is why we have undertaken the study of cyclic dipeptides, both in the gas phase and in the condensed phase, with the aim of evidencing chirality-induced structural differences.26 Cyclic dipeptides result from the intramolecular peptide coupling of a linear α dipeptide.27-29 They all contain a Diketopyperazine (DKP) ring and are an important class of dipeptides with applications as active pharmaceutical ingredients.30,31 Cyclic dipeptides are often more stable than their linear counterpart in vivo and therefore promising in terms of therapeutic application.31 The DKP ring conformation depends on the nature of the residues and can be either planar, boat, or chair.32,33 34-36 A planar conformation is only observed for dipeptides molecules with small side groups like Glycine.37 The conformation remains planar for the slightly larger alanine (Ala) residue when the two residues are of opposite chirality, namely cyclo LAla-DAla. However, it becomes puckered for cyclo (LAla-LAla).33 Cyclic dipeptides containing a bulky residue like phenylalanine and tyrosine have a preferred conformation in which the aromatic ring in the side chain stacks over the DKP ring and the ring adopts a boat form.38 2 ACS Paragon Plus Environment

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This work aims at determining the structural and spectroscopic differences due to chirality for the two diastereomers of a protonated DKP dipeptide built on phenylalanine (Phe). The studied systems, namely, protonated cyclo (LPhe-LPhe), referred to as c-LLH+, and cyclo (LPhe-DPhe), referred to as c-LDH+, are shown in Figure 1. The gas-phase structure of the neutral peptides has been studied already, as well as that of the cyclo (LPhe-LPhe) crystal.26,36 The gas-phase neutral molecules display a boat conformation, with one Phe extended towards the amide nitrogen while the other one is stacked over the DKP ring. Due to the aromatic nature of phenylalanine, dispersion forces are important in the stabilization of the peptide and may favor OH… π,39-41 NH…π,42 or CH…π43,44 non-covalent interactions, which have been suggested to play a role in chiral recognition.19,45 The two diastereomer dipeptides are studied by combining Fourier transform ion cyclotron resonance (FTICR) mass spectrometry with laser spectroscopy.46 The vibrational signature of the studied systems is obtained by means of infrared multiple photon dissociation (IRMPD) spectroscopy and compared to quantum chemical calculations. Both fingerprint (1000-1800 cm-1) and OH or NH stretch (3100-3700 cm-1) regions are explored. IRMPD spectroscopy has been shown indeed to be a powerful tool for studying the structure of peptides, for example protonated peptides47-50, their complexes with alkali metals47 or divalent and trivalent metals,51,52 their cation or anions,53 as well as their reaction products54 or their derivatives with post-translational modifications.55-57 Studies of DKP peptides are limited to the protonated model systems, cyclo GlyGly58,59, cyclo AlaGly,60 and linear PhePhe in interaction with Ca2+.61

2. Methods 2.1. Experimental section The experiment setup has been described in details already and is only briefly summarized here.46 It involved a 7T Fourier FT-ICR hybrid mass spectrometer (Bruker, Apex Qe) coupled to a Free Electron Laser (FEL) at the Centre Laser Infrarouge d’Orsay (CLIO).62 The protonated species were generated by electrospraying a 100 μM solution obtained by diluting a 1 mM stock solution into a slightly acidified (1% formic acid) mixture of methanol and water (50:50). The cyclic dipeptides were obtained from GeneCust- Luxembourg (98% purity) and used without further purification. Infrared spectra were obtained by monitoring the fragmentation efficiency φ= -ln(P/(F + P)) as a function of the IR wavelength, with F being the sum of the abundances of the fragment ions produced by IRMPD and P that of the parent. The 900-2000 cm-1 region was covered resorting to the CLIO FEL.62 The CLIO FEL beam was mildly focused by a 2000 mm Ag-protected spherical concave mirror, with a typical beam waist at the centre of the FT-ICR of the order of 1 mm diameter. The CLIO FEL operated at 25 Hz with 8 µs long bunch pulses containing 0.5-3 ps micropulses separated by 16 ns. The spectral bandwidth (full width at half maximum FWHM) was about 7 cm-1 with pulse energy of 1600 to 900 mW from 900 to 2000 cm-1. The wavelength calibration was ensured by simultaneously recording the spectrum of polystyrene. The irradiation time was 1s. Additional broadband CO2 laser synchronized with CLIO (Universal Laser system 10 W at cw operation centered at λ = 10.6 μm) was employed to sustain the fragmentation. The CO2 laser pulse length was adjusted to 3.8 ms to avoid photo-dissociation of the molecule by the CO2 laser alone.



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The vibrational spectrum in the OH and NH stretch region was recorded resorting to an IR Optical Parametric Oscillator laser (LaserVision OPO, 25 Hz, 5-10 mJ/pulse). The irradiation time was 3 s and the CO2 laser pulse length was adjusted to 30 ms.

2.2. Computational details Exploration of the potential energy surface (PES) was performed using the OPLS-2005 and MMFFs force fields with the advanced conformational search implemented in the MacroModel suite, a part of the Schrödinger package.63 All the peptides structures found thereby with energy below 20 kJ/mol were optimized within the frame of the DFT theory at the b97-d3 /TZVPP level of theory, using the resolution of the identity approximation for the evaluation of the electron-repulsion integrals in order to decrease the calculation time.64 The conformers of the most stable family, namely, those protonated on oxygen (vide infra), were re-optimized using the dispersion-corrected functional B3LYP-D3 associated to the 6-311G++(d, p) basis set. The B3LYP-D3 functional was chosen here, as it was in previous studies,65,66 because it combines the good frequency description of the hybrid functional B3LYP67 and inclusion of empirical dispersion corrections, which might be important for peptides containing aromatic residues.68,69 Indeed, calculation of the interaction energy between neutral or protonated alanine and benzene indicate that methods taking dispersion into account are necessary to reproduce the OH…π, NH…π, and CH…π, interactions.70 To make sure that the whole PES was fully explored, structures were also built from the most stable neutral conformers found previously.26 A proton was added to each of the two oxygens, with the two possible orientations of the OH, and the resulting structure was optimized as described above. The vibrational spectra were simulated by convoluting the harmonic frequencies obtained at the same level of calculation by a Lorentzian line shape (FWHM 10 cm-1). A scaling factor of 0.970 in the 900-1700 cm-1 region and 0.955 in the 3000-3800 cm-1 region was applied to correct the frequencies for anharmonicity and basis set incompleteness. All calculations were performed with the Gaussian 09 packages71 or with the Turbomole 6.6 software.72

3. Results and discussion 3.1. CID fragments MS2 Collision-Induced Dissociation (CID) spectra of c-LLH+ and c-LDH+, obtained in the hexapole collision cell with a collision voltage of -6.5 V, are displayed in Figure 2. Both systems show similar fragmentation pattern and efficiency. For an activation time of 0.2 s, loss of CO (m/z 267) and formation of the iminium ion of Phe (m/z 120) are observed as the major fragmentation channels. For longer activation time, sequential fragmentation is observed. Subsequent loss of NH3 and CO from m/z 267 results to the m/z 250 and m/z 222 fragments. The fragmentation pattern described above is typical of DKP dipeptides.73-75 A mechanism has been proposed for model protonated DKP based on Glycine and Alanine, which involves either fragmentation from the most stable Oprotonated tautomer, in the case of cyclo AlaAla, or isomerization to the N-protonated tautomer with subsequent fragmentation, in the case of cyclo GlyGly.76 Minor differences in the fragments relative intensity are observed in c-LDH+ relative to cLLH+. While the primary fragments (m/z 267, m/z 120) are slightly more intense in c-LLH+, the


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secondary fragments are slightly more intense in c-LDH+ .This observation indicates that c-LDH+ has slightly larger fragmentation efficiency.

3.2. IRMPD Spectra

The IRMPD spectra of LLCH+ and LDCH+ are presented in Figure 3. Their aspect is similar on the overall spectral range; they show however minor differences. The fingerprint region is dominated by an intense and congested feature in the region of the β(OH) and aliphatic β(CH) bending modes, which looks identical for the two diastereomers, with two maxima at at 1270-1310 cm-1 in c-LLH+ and 1280-1312 cm-1 in c-LLH+. The β(NH) range displays two bands of weak intensity at 1440 cm-1 and +

1493 in c-LDH+, whose counterpart seems to overlap in c-LLH , at 1452-1492 cm-1. Last, the ν(CO) stretch region is characterized by two intense bands located at 1674-1734 cm-1 in the c-LDH+ +

spectrum, and at 1681-1750 cm-1 in that of c-LLH . These bands are typical of the amide I vibration mode of protonated DKP rings.59 In the fingerprint region, the main differences between the two diastereomers is the blue shift of several bands of c-LLH+ relative to c-LDH+. The high frequencies region is characterized by two features identical for the two diastereomers: First, a broad and intense absorption that peaks at ~ 3250 cm-1 and extends from 3050 to 3350 cm-1. Second, an intense and narrow peak appears at 3415 cm-1. The main differences appear on the one hand in the ν(OH) stretch region where the spectrum of c-LDH+ shows two peaks at 3592 and 3564 cm-1, while that of c-LLH+ only shows a broadened peak at 3567 cm-1. Last, a peak appears at 3380 +

cm-1 in the spectrum of c-LDH+ while it is absent in that of c-LLH .

3.3. Theoretical results and assignment The nomenclature used for the molecule is shown in Figure 1. The peptide bond atoms will be referred to with a subscript “p” when they are on the protonated part. The carbon atoms of the residue will be denoted by their position relative to the peptide bond, i.e. Cα or Cβ. Last, the ipso carbon of the benzene rings will be denoted by the subscript “i”. Two protonation sites can be considered, namely, protonation of the amide oxygen and protonation of the amide nitrogen. For both c-LLH+ and c-LDH+ the most stable structures correspond to protonation of the oxygen atom. The most stable conformer protonated on the amide nitrogen is higher in energy, by about 13 kcal/mol, than the most stable conformer protonated on the amide oxygen. It is therefore unlikely that it is populated in our experimental condition at room temperature. The most stable N-protonated structures are shown in Figure S1 of the Supplementary Information. Moreover, the calculated spectra of the N-protonated species do not show satisfactory agreement with the experimental results, as shown in Figures S2 and S3 of the Supplementary Information. These conclusions are in line with proton affinity measurements resting on the Cooks kinetic method77 that indicate a larger stability of the O-protonated form of cyclic peptides due to the formation of a resonance stabilized cation.78 This results also parallel those deduced from the IRMPD spectra of the most simple DKP dipeptide, cyclo GlyGly.58



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The most stable conformers of c-LDH+ and c-LLH+ are presented in Figure 4 and the relative Gibbs energies given in Table 1. The energetic characteristics obtained at the B97-D3/TZVPP level are identical to those at the B3LYP-D3/6-311++g(d,p) level and are summarized in Table S1 of the Supplementary Information. In what follows, we will describe the B3LYP-D3 only. The most stable conformation of c-LDH+, CLD0, is stabilized by two interactions involving the aromatic ring. An ionic OpH…π interaction is accompanied by a neutral CαpH…π interaction. These interactions result to short distances of 2.51 (2.53) Å between OpH (CpH) and the center of the aromatic ring. The CLD1 conformation (1.6 kcal/mol) also shows an ionic OpH…π interaction, but the CαpH…π interaction is missing and is replaced by a NpH…π interaction. CLD2 and CLD3 both involve intramolecular NpH…π and CαH…π interactions but differ by the orientation of the OH group. Despite the resonance stabilization of the cation, the NpH…π interaction is less stabilizing than the OpH…π, which explains that CLD2 and CLD3 are higher in energy than the conformers that involve an OpH…π interaction, by a few kcal/mol. The NpH…π interaction is characterized by a distance between NpH and the center of the ring of more than 3 Å (3.06 Å for CLD2 for example). The two peptide bonds of the molecule are now different because of the dissymmetry introduced by protonation of one of the amide oxygens. This manifests itself by different NH bond lengths: 1.013 Å for the NH on the neutral side, vs. 1.17 to 1.025 Å on the protonated side depending on whether NpH is involved in an hydrogen bond or not. However, the amide bond remains planar or quasi planar (dihedral angle < 5°) in all cases. In the most stable conformer CLD0, the non-protonated amide bond is very similar to what is observed or calculated for the neutral molecule. The DKP ring structure is slightly puckered. It shows a flattened boat structure with a puckering angles of ~-10°, similar to that of the neutral molecule (-11°).36 One of the aromatic rings is in a flagpole position, which corresponds to an NCαpCβpCip dihedral angle of ~60°, very close to what is calculated for the neutral molecule (65°). The ~60° angle allows CH…π interaction to take place. In contrast, the NCαCβCi dihedral angle calculated for the Phe in extended position is of the order of 180°, very different from the −58° calculated in the neutral (unpublished results). This is due to a rotation of the phenyl that allows optimization of the OpH…π interaction. The other conformers differ from the most stable by the DKP structure, much closer to planarity, and the residue conformation. The NCαCβCi dihedral angle of ~180° or ~60° correspond to OpH…π (LCD1) or CαH…π (CLD2 and CLD3) interactions, respectively, while the NCαpCβpCip dihedral angle of ~55° corresponds to an NpH…π interaction. +

The results obtained for c-LLH parallel those described for c-LDH+ with however minor differences. CLL3 differs from CLD3 and stands out by the nature of the CH…π and NH…π interactions. While the NH…π interaction involves NpH on the protonated side in CLD3, it involves NH on the neutral side in CLL3 and is therefore weaker (distance between NH and the center of the ring of 3.3 Å). Conversely, CLD3 displays a CαH…π interaction while CLL3 shows a CβH…π interaction. The calculated Gibbs energy of the most stable structures, namely CLD0 and CLL0, indicates that CLL0 is more stable by 0.17 kcal/mol. at the B3LYP-D3/6-311++g(d,p) level. The calculated difference is within the error and one cannot draw definitive conclusions from these numbers. The experimental IRMPD spectrum of c-LDH+ and the spectra simulated for CLD0, CLD1, CLD2 and CLD3 at the B3LYP-D3/6-311++g(d,p) level of theory are presented in Figure 5. A tentative assignment of the main IRMPD features of c-LDH+ is proposed in Table 2 by comparing the experimental vibrational frequencies with those calculated for the IR active vibrational modes. Comparison with the B97-D3/TZVPP results is given in Figures S4 and S5 of the Supplementary 6 ACS Paragon Plus Environment

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Information. The agreement with the experimental data is slightly better at the B3LYP-D3/6311++g(d,p) level and only the latter results will be discussed. The highest-energy peaks observed in the experimental spectrum at 3564 and 3592 cm-1 are typical of free ν(OH) stretches. They appear in the same frequency range as the ν(OH) stretch observed by Wang et al. in the model protonated DKP, cyclo (GlyGly)H+, at 3585 cm-1.58 The 3564 and 3592 cm-1 bands can therefore be assigned to the free ν(OpH) stretch of CLD3 and CLD2, respectively. Their relatively weak intensity results from the low population of CLD2 and CLD3. It must be noted that the band assigned to the ν(OH) stretch dominates the spectrum of cyclo (GlyGly)H+, the other bands being one order of magnitude less intense. The other bands expected for CLD2 and CLD3 are therefore not expected to be detectable and the other features observed in the spectrum must be due to CLD0 and CLD1.79 It must be noted that a Maxwell-Boltzmann distribution at room temperature predicts negligible population of CLD3 and CLD2 compared to CLD0 (see Table 1), which should be the only conformer substantially populated. Kinetic trapping explains the presence of thermodynamicallydisfavored species, as already observed in mass spectrometry experiments involving an electrospray source.80-82 Another possibility would be incorrect description of the energy ordering, possibly due to imperfect description of dispersion. The doublet at 3380-3415 cm-1 is characteristic of the ν(NH) stretches of the protonated DKP ring. In cyclo (GlyGly)H+, the amide ν(NH) stretches appear at 3370 and 3430 cm-1 for the protonated and neutral amide, respectively. The peaks at 3380-3415 cm-1 are attributed to their counterpart in CLD0, possibly superimposed with the ν(NH) stretch of CLD1, which is located at the same position a that CLD0. The broad and intense band between 3350 and 3050 cm-1 is assigned to the ν(OpH) stretch of CLD0, possibly superimposed with that of CLD1. The broadening and the red shift of the band are due to the interaction between OpH and the π electron of the aromatic ring. The fingerprint region is not very specific: the superposition of the spectra simulated for the two most stable conformers yield satisfactory agreement with the experiment. Contribution of LD2 and LD3 is also compatible with the observed spectrum. The CO stretch appears at 1734 cm-1 while the other intense band at 1674 cm-1 is due to the ν(CpNp) stretch, which gains intensity due to the charge. These bands are typical of the amide I in protonated DKP rings.59 Indeed, this spectral region does not look the same for protonation on N (see Supplementary Information). The two partly resolved bands around 1480 cm-1 contains the contribution of the β(NH) and β(CH) bend, which gains intensity via the OH…π interaction. The intense feature at ~1280 cm-1 contains the contribution of multiple β(CH) bends, the most intense being the β(CαH). It should be noted that the bands due to the CO stretches are not as strong in the experimental spectrum as theoretically predicted, as often observed in peptides an DNA basis.24,83 The results for cLLH +, shown in Figure 6, parallel those for c-LDH+ and we will only stress the differences between them. The fingerprint region only shows minor differences that are difficult to interpret. In the high-energy region, the bands assigned to the ν(OH) stretches of CLL2 and CLL3 are closer to each other, which explains that the feature appearing as a distinct doublet in c-LDH+ is now a single band with a shoulder. The NH stretch region displays a single band, which contrasts with the doublet observed for c-LDH +. This is due to the fact that the OH…π interaction is weaker in CLL0 than in CLD0. As a result, the ν(OH) stretch is less intense and less shifted and overlaps with the ν(NH)



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stretching mode located on the NH far from the protonation site, which is therefore hidden and does not appear in the spectrum.

4. Conclusion The diastereomers of a protonated cyclic dipeptide built on phenylalanine have been structurally characterized by IRMPD spectroscopy in two spectral regions, 1000-1800 cm-1 and 3000-3700 cm-1, combined with DFT calculations. Experimental findings, especially in the fingerprint region, and theoretical results unambiguously show that protonation happens on the amide oxygen for both c-LDH+ and c-LLH+. In particular, the amide I stretch region is typical of the DKP ring protonated on the oxygen. The experimental spectra can be satisfactorily reproduced only by taking into account the presence of the four most stable conformers, kinetically trapped in our experimental conditions. The DKP ring structure is slightly puckered and takes a dissymmetrical geometry due to protonation. The most stable form shows a DKP ring geometry close to that of the neutral form, namely a flattened boat geometry, for both c-LDH+ and c-LLH+. The chirality of the residues does not have dramatic influence on the molecular structure. However, c-LDH+ and c-LLH+ differ by the strength of the intramolecular OpH…π hydrogen bonds, which results in differences in the ν(NH)/ν(OH) stretch region. The higher energy conformers display a wide range of intramolecular hydrogen bonds, namely, OpH…π (CLD1 and CLL1) or CαH…π (CLD2, CLD3 and CLL2) accompanied by an NpH…π interaction. CLL3 stands out and differ from its CLD3 counterpart by showing CβH…π and NH…π interactions. The fragmentation efficiency is slightly larger for c-LDH+ than for c-LLH+, which is compatible with slightly smaller formation energy for CLD0 than for CLL0. However, the difference is within the error and one cannot rule out kinetic effects. 84-86 Experiments in cryogenic ion traps are in progress for better differentiation of the diastereomer cyclic dipeptides.87,88

5. Supporting Information In this section are shown the geometry and energetics of higher-energy conformers of c-LDH+ and c-LLH+, protonated on N, as well as their simulated IR spectra. This section also gives the spectra and energetics of the conformers discussed above calculated at the b97-D3/TZVPP level of theory.

6. Acknowledgments The research described here has been supported by the “Investissements d’Avenir” LabEx PALM contract (ANR-10-LABX-0039-PALM) and by the ANR contract (ESBODYR ANR-14-CE06-0019-03). Dr. Philippe Maître and the mass spectrometry platform SMAS of the Laboratoire de Chimie Physique (Univ. Paris-Sud) are gratefully acknowledged. We thank Dr J. M. Ortega and the CLIO team for technical assistance. We acknowledge the TGE FT-ICR ((FR 3624) for financial support and the use of the computing center MésoLUM of the LUMAT research federation (FR LUMAT 2764).

7. References


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Page 14 of 22

Figure and tables Table 1: Relative electronic energies (ΔE) and Gibbs energies (ΔG) at room temperature (298 K ) in kcal/mol calculated at the B3LYP-D3/6-311++g(d,p) level of theory. Calculated (NH) and (OH) distances (Å) and relevant angles (°).

ΔE (kcal/mol) B3LYP-D3/6311++g(d,p)

ΔG (kcal/mol) Boltzmann B3LYP-D3/6factor 311++g(d,p) (% )

CαpCpNpCα dihedral angle (°)

CαCNCαp dihedral angle (°)

NCαCβCi dihedral angle (°)

NCαpCβpCip dihedral angle (°)

d(Np…H) d(OpH) (A°) (A°)

CLD0

0.0

0.0

93

-16

-11

+174

61

1.017

0.988

CLD1

3.8

1.6

6

9

2

-170

56

1.022

0.985

CLD2

4.1

2.8

1

-16

-2

61

54

1.024

0.968

CLD3

4.8

3.8

Does the Residues Chirality Modify the Conformation of a Cyclo

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