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Molecular Dynamics Study of Nitrogen-Pyramidalized Bicyclic #-Proline Oligomers. Length-Dependent Convergence to Organized Structures Yuko Otani, Satoshi Watanabe, Tomohiko Ohwada, and Akio Kitao J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.6b10668 • Publication Date (Web): 05 Dec 2016 Downloaded from http://pubs.acs.org on December 10, 2016

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The Journal of Physical Chemistry

Molecular Dynamics Study of Nitrogen-pyramidalized Bicyclic β-Proline Oligomers. Length-dependent Convergence to Organized Structures

Yuko Otania, *, Satoshi Watanabea,b, Tomohiko Ohwadaa, Akio Kitaoc,*

a

Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan b

National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashimachi, Kodaira-shi, Tokyo 187-8551, Japan

c

Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan

* Corresponding Authors: Dr. Yuko Otani Graduate School of Pharmaceutical Sciences, The University of Tokyo 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan TEL: +81-3-5841-4732 E-mail: [email protected] Dr. Akio Kitao Institute of Molecular and Cellular Biosciences, The University of Tokyo 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan TEL: +81-3-5841-2297 E-mail: [email protected]

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Abstract In this study, the solution structures of the homooligomers of a conformationally constrained bicyclic proline-type β-amino acid were studied by means of molecular dynamics (MD) calculations in explicit methanol and water using the umbrella sampling method. The ratio of trans-amide and cis-amide was estimated by NMR and the rotational barrier of the amide of acetylated bicyclic amino acid monomer was estimated by two-dimensional (2D) exchange spectroscopy (EXSY) or line-shape analysis. A bias potential was introduced with respect to the amide torsion angle 𝝎 to enhance conformational exchange including isomerization of amide bonds by lowering the rotation energy barrier. After determination of reweighting parameters to best reproduce the experimental results of the monomer amide, the free energy profile around the amide torsion angle w was obtained from the MD trajectory by reweighting of the biased probability density. The MD simulation results support the existence of invertomers of nitrogen-pyramidalized amide. Furthermore, extended structures with a high fraction of trans-amide conformation appear to be increasingly stabilized as the oligomer is elongated, both in methanol and in water. Our conformational analysis of natural and non-natural tertiary-amide-based peptide oligomers indicates that these oligomers preferentially adopt a limited number of conformations.


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1. Introduction Natural or non-natural oligopeptides that form stable regular structures can be useful scaffolds for mimicking biological functions of natural biomolecules and understanding protein folding mechanisms.1-4 Incorporation of residues with cyclic structures is often effective for stabilization of well-organized structure in short oligomers.

5-10

Above all, oligopeptides containing conformationally constrained

proline-analogs are considered as promising scaffolds.11-18 Although they have tertiary amide bonds, which are in equilibrium between trans-amide and cis-amide, the constraints on their main-chain conformations mean that these conformations are less likely to be affected by environmental factors. Natural α-proline oligomers can take regular structures upon elongation, i.e., polyproline I (PPI) helix with all-cis amide structure, and polyproline II (PPII) helix with all-trans amide structure,19 both of which are distinct from typical hydrogen-bonding α-helix and β-sheet structures. α-Proline oligomers tend to take the extended PPII structure in water, and thus they can be applied as molecular rulers.

20-25

However, it is often difficult to investigate the solution structures of such oligomers due to limited information on inter-residue NOEs, slow inter-conversion between cis and trans amide conformers of tertiary amides, and conformational change of the pyrolidine ring. The trans-amide in the PPII structure is stabilized by steric repulsion and orbital interaction between neighboring amide bonds.26-29 A recent crystal structure analysis of α-proline hexamer confirmed the above interactions at the atomic level.30 3 ACS Paragon Plus Environment


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The monomeric α-proline amide (N-acetyl-L-proline-NHMe) favors trans-amide conformation with a trans:cis ratio of approximately 73:27 in D2O.31 Although recent studies suggest that α-proline oligomers longer than pentamer take almost entirely all-trans conformation in water and in chloroform,

32-34

the fraction of cis-amide

structure in oligomers from the dimer to the tetramer (or pentamer) remains controversial. On the other hand, there has been increasing interest in oligomers of β-amino acids, i.e., β-peptides, because they can form stable regular structure and are stable to proteolytic degradation. Oligopeptides of non-natural β-proline and its analogues can also adopt ordered structures.

35-39

However, control of the amide cis-trans equilibrium

in oligomers of β-proline analogs is often less effective than in α-proline oligomers. This is because neighboring amide bonds are distal and electronic interaction between them is weak, and in addition, both amide conformations have similar degrees of steric repulsion. However, peptide homooligomers of β-amino acids bearing the bicyclic 7-azabicyclo[2.2.1]heptane skeleton (7-azabicyclo[2.2.1]heptane-2-carboxylic acid, Ah2c, Figure 1), which is a conformationally constrained β-proline analog, have been synthesized (2a, 3a, 4a, and 5a, Figure 1).40 A derivative of dimer 2a with a tBuOCO （Boc） group at the N-terminal and a N-methylamide at the C-terminal exhibits trans-cis equilibrium with a slight preference for the trans form (trans : cis = 55:45 in CDCl3), although detailed solution structural analysis of oligomers longer than the dimer was hampered by line-broadening of NMR signals due to slow interconversion between amide rotamers. Furthermore, the bicyclic amide takes a nonplanar structure in 4 ACS Paragon Plus Environment

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solution, and the amide is tilted to either side of the amide plane (formed by the amide nitrogen and two bridgehead carbons).41 The experimental circular dichroism (CD) spectra of the hydrochloride salts of unprotected oligopeptides (2a, 3a, 4a, and 5a) in methanol were also reported.40 They showed characteristic and intense CD with the minimum at around 198 nm and the maximum at around 217 nm, and an isodichroic point at around 206 nm. Furthermore, the intensity per residue at the maximum increased length-dependently. These observations suggested that thermodynamically stable regular structure could be induced as the oligomer is elongated. However, further investigation is needed to enable the assignment of major structures in solution. Molecular dynamics simulation is a powerful tool to investigate the solution conformation of peptides and proteins. Various kinds of simulation methods, such as accelerated MD,42 steered dynamics,43 adaptively biased MD,43 replica exchange MD,44 and metadynamics,45,46 have been applied for conformation sampling of proline-type oligopeptides with tertiary amides, in order to overcome the high energy barrier of amide bond rotation. 47 As the bicyclic ring of the β-amino acid scaffold helps to constrain the main-chain conformation, and the conformational freedom of these oligomers is relatively limited, we considered that a simpler and less computationally demanding simulation method might be suitable for thorough conformational search. Methodology to calculate CD spectra in solution has recently been developed, and can be applied to flexible systems such as oligopeptides.48,49 Thus, we expected that CD spectra of β-peptide oligomers could be predicted by averaging the calculated spectra of 5 ACS Paragon Plus Environment


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conformers according to the probability of their formation. In this work, we estimated the rotational barrier of the monomeric amide of bicyclic β-proline by NMR spectroscopy and performed MD simulation of homooligomers with an umbrella sampling method50,51 to accelerate amide bond rotation and to enable sampling of a wide range of conformations. We found that as the oligomer is elongated, the ratio of trans-amide bonds increases, which implies that extended helical structures are stabilized. This scenario is consistent with the observed CD spectra, in which the intensity of the signal per residue increases as the oligomer is elongated.

(a)


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pentamer R1 N

tetramer R1

O N

N

trimer R1

O

O

N

N

N

dimer R1

O

O

O

N

N

N

N

monomer R1

O

O

N

O

R1 = H·HCl, R 2 = OH

N

O

O

O

R2

N

N

O

R2

O

O

N

R2

R2

R2

1a

2a

3a

4a

5a

R1 = CH 3CO, R 2 = NHCH 3 1b

2b

3b

4b

5b

(b) N O ω = 180°

N O ω = 0°

N

O

N

O cis

trans

Figure 1. (a) Structures of homooligomers of (S)-Ah2c and (b) amide trans-cis equilibrium of the Ah2c oligomer.



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2. Materials and Methods 2-1. Synthesis of monomer 1b Monomer (1b), which has an acetyl group on the nitrogen and an N-methyl amide group as a C-terminal carboxamide group, was synthesized from the N-Boc-protected β-amino acid40 in three steps (see Supporting Information). 2-2. NMR spectroscopy. NMR spectra of 1b were recorded at the concentration of 25 mM in methanol (CD3OD) and water (D2O) on a Bruker Avance 400 MHz spectrometer. The amide cis-trans equilibrium of 1b in methanol (CD3OD) and water (D2O) was studied by 1H-NMR spectroscopy. Because line-shape fitting did not reproduce the experimental 1H-NMR spectra in CD3OD well, we chose 2D exchange spectroscopy (EXSY)52-54 to estimate the amide rotational barrier. The EXSY spectra of 1b were recorded with mixing times of 100, 200, 300, 400, 500, and 600 ms over the temperature range of 287.3 - 326.5 K. The temperatures were calibrated with ethylene glycol as a reference by using a standard method.55 The signal intensities of the four peaks due to one pair of exchanging bridgehead protons were obtained from the peak height (Figure 2): Itt is the peak intensity of the auto peak of Hd in the trans conformation, Icc is that of the auto peak of Hb in the cis conformation, Itc is that of the cross peak from the trans to cis conformation, and Ict is that of the cross peak from the cis to trans conformation. They were acquired with 6 mixing times, Tm. The exchange rate from trans to cis conformation (ktc) and that from cis to trans conformation (kct) at each temperature were estimated by fitting to a modified version of 8 ACS Paragon Plus Environment

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the theoretical equation reported previously. 56 𝐼!! 𝑇! =

𝐼! 0 − 𝜆! − 𝑥! 𝑒 !!! !! + 𝜆! − 𝑥! 𝑒 !!! !! 𝜆! − 𝜆!

𝐼!! 𝑇! =

𝐼! 0 − 𝜆! − 𝑥! 𝑒 !!! !! + 𝜆! − 𝑥! 𝑒 !!! !! 𝜆! − 𝜆!

𝐼!" 𝑇!

−𝐼! 0 𝑘!" 𝑒 !!! !! − 𝑒 !!! !! = 𝜆! − 𝜆!

𝐼!" 𝑇! =

−𝐼! 0 𝑘!" 𝑒 !!! !! − 𝑒 !!! !! 𝜆! − 𝜆!

where λ1,2, xt and xc are defined according to the following relationships 𝜆!,! =

𝑥! + 𝑥! ±

𝑥! − 𝑥! 2

!

+ 4𝑘!" 𝑘!"

𝑥! = 𝑅!! + 𝑘!" 𝑥! = 𝑅!! + 𝑘!" R1t is the longitudinal relaxation rate in the trans conformation and R1c that in the cis conformation, which were set as variables. Rate constants at various temperatures were obtained (Figure S5) and the free energy of rotation was derived from the slope and intercept of the Eyring plot (Figure S6): ln

! !

=−

Δ! ‡ !"

+

Δ!‡ !

+ ln

!! !

,

where T is the temperature, R is the gas constant (1.98719 cal·K-1·mol-1), kB is the Boltzmann constant (3.29986 x 10-24 cal·K-1), and h is Planck’s constant (1.58369 x 10-34 cal·s). Parameters were obtained from unbiased estimates of the standard deviations of least-squares parameters and are reported at the 95% confidence level. ∆G‡ was obtained from the following equation: ∆G‡ = ∆H‡ - T∆S‡, and errors in ∆G‡ values were 9 ACS Paragon Plus Environment


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evaluated as the sum of the errors in ∆H‡ and the product of those in ∆S‡ and T.57 In the case of the rotational barrier in D2O, line-shape analysis successfully reproduced the 1H-NMR peaks of two sets of exchanging bridgehead protons in 1b, which enabled us to estimate the rate constant at each temperature (Figure S7). Line shape analysis was carried out with DNMR software (Bruker Biospin) and was performed by iterative matching of simulated spectra with the experimental spectra. The free energy of rotation was derived from the slope and intercept of the Eyring plot (Figure S8). Parameters were obtained from unbiased estimates of the standard deviations of least-squares parameters and are reported at the 95% confidence level. 57 2-3. Computational method 2-3-1. MD simulation with a bias potential and free energy calculation with umbrella sampling MD simulations of homooligomers 1b to 5b were conducted to sample the conformational space of Ah2c oligomers. The sampled structures are analyzed and classified with respect to the torsion angle ω (C (i+1)-C(i+1)-Ni -C i) of the amide bond α

α

which connects neighboring Ah2c residues (Figure 4): when ω is in the range of −90°
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Giorgio, E.; Tanaka, K.; Ding, W.; Krishnamurthy, G.; Pitts, K.; Ellestad, G. A.; Rosini, C.; Berova, N. Theoretical Simulation of the Electronic Circular Dichroism Spectrum of Calicheamicin. Bioorganic Med. Chem. 2005, 13, 5072–5079.


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The final values of parameters in Eq. (7) are 𝑉! = -0.1 kcal/mol and 𝑉! = 8.5 kcal/mol.

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As it is reported that the TD-DFT with the B3LYP functional tends to underestimate the excitation energies of transition (ref. 48), TD-DFT calculation at the level of IEFPCM (methanol)-CAM-B3LYP/def2TZV was also performed. However, none of the signals of rotamers of 2a, 3a, and 4a resembled the experimental CD spectra. (Figure S12).

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Hosoya, M.; Otani, Y.; Kawahata, M.; Yamaguchi, K.; Ohwada, T. Water-Stable Helical Structure of Tertiary Amides of Bicyclic β-Amino Acid Bearing 7-azabicyclo[2.2.1]heptane. Full Control of Amide Cis-Trans Equilibrium by Bridgehead Substitution. J. Am. Chem. Soc. 2010, 132, 14780–14789.

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Wang, S.; Otani, Y.; Liu, X.; Kawahata, M.; Yamaguchi, K.; Ohwada, T. Robust Trans-Amide Helical Structure of Oligomers of Bicyclic Mimics of β-Proline: Impact of Positional Switching of Bridgehead Substituent on Amide Cis-Trans Equilibrium. J. Org. Chem. 2014, 79, 5287–5300.



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Molecular Dynamics Study of Nitrogen ... - ACS Publications

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