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Conformational Study of Two Linear Hexapeptides by Two-Dimensional NMR and Computer-Simulated Modeling: Implication for Peptide Cyclization in Solution

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Conformational Study of Two Linear Hexapeptides by Two-Dimensional

NMR and Computer-Simulated Modeling: Implication for Peptide

Cyclization in Solution

Aih-Jing Chiou,* Geok-Toh Ong,† Kung-Tsung Wang,† Shyh-Horng Chiou,*

,

† and

Shih-Hsiung Wu*

,

,1

*Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan; and †Institute of Biological Chemistry, P.O. Box 23-106, Academia Sinica, Taipei, Taiwan

Received January 3, 1996

Two linear peptides, D-leucyl-L-prolyl-L-isoleucyl-L-valyl-L-alanyl-b-alanine (I) and D-leucyl-L-prolyl-L -isoleucyl-L-valyl-N-methyl-L-alanyl-b-alanine (II), whose sequences were designed from protodestruxin and desmethyldestruxin B by replacingD-leucic acid withD-leucine, two cyclic hexadepsipeptides with insecticidal and immunodepressant activities, have been found to be cyclized in unusually high yields (>85%). In order to gain insight into the conformation and the relative flexibility of different constituent residues in these linear peptides, we have applied various techniques of 2D-NMR spectroscopy coupled with dynamic simulated an-nealing by computer modeling to establish the solution conformations of these two linear peptides. Based on the derived structures, it is found that the distances betweenN- andC-terminal residues of both peptides are short enough to facilitate the cyclization, thus collaborating the observation of favorable cyclization yields for both linear peptides. © 1996 Academic Press, Inc.

Cyclic peptides with ring structure from natural products are well known to play important roles

in their biological activities. A lot of microbial peptides such as peptide antibiotics possess

struc-ture-constrained ring structure [1]. Since the synthesis of gramicidin S was accomplished in 1950s,

many cyclization methods including both the cyclization and cleavage of peptides on the

solid-phase resins have been developed [2,3]. For a successful chemical synthesis of biologically-active

cyclic peptides, the key step is usually the cyclization reaction. In most cyclization reactions of

synthetic peptides, lower yields are obtained [4]. The yield of cyclization for linear peptides

depends on several factors such as sequence and length of linear peptides, concentration of linear

peptides, reagents and conditions of cyclization [2,5], etc.

Destruxins are cyclic hexadepsipeptides first isolated from the culture filtrate of Metarrhizium

anisopliae, an insect-pathogenic fungus [6]. They are composed of 5 amino acids:

L

-Pro,

L

-Ile,

N

-methyl-

L

-Val,

N

-methyl-

L

-Ala and

b

-alanine plus a

D

-

a

-hydroxy acid which differs in five

congeners, destruxins A, B, C and D. and desmethyldestruxin B [6–8]. Destruxin B and

desmeth-yldestruxin B are proposed to be biosynthesized from protodestruxin by

N

-methylation at two sites

and subsequent demethylation at one site on the cyclic ring [9].

Our recent interests in these conformation-constrained cyclodepsipeptides lie in their potential

application as useful immunodepressants similar to cyclosporins [10] plus their suppressive effect

on hepatitis B virus surface antigen (HBsAg) production in human hepatoma cells [11]. In an effort

Abbreviations: NMR, nuclear magnetic resonance; BOP, benzotriazolyloxycarbonyl N-oxytridimethylamino-phosphonium hexafluorophosphate; DQF-COSY, double-quantum filtered correlation spectroscopy; HOHAHA, homo-nuclear Hartmann-Hahn spectroscopy; XH-COSY, heterohomo-nuclear shift-correlated spectroscopy; NOESY, homo-nuclear Over-hauser and exchange spectroscopy; ROESY, rotating frame nuclear OverOver-hauser and exchange spectroscopy; NOE, nuclear Overhauser effect; RMSD, root mean square deviation; DMF, dimethylformamide; DMSO, dimethylsulfoxide; HMP resin, p-hydroxymethylphenoxymethylpolystyrene resin; Fmoc-amino acid, N-fluorenylmethoxycarbonyl-amino acid.

1Corresponding address: Institute of Biological Chemistry, Academia, P.O. Box 23-106, Taipei, Taiwan. Fax: (886)-2-3635038. E-mail: shwu@gate.sinica.edu.TW.

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS219, 572–579 (1996)

ARTICLE NO. 0275

572 0006-291X/96 $18.00

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to prepare useful analogues of these biologically active cyclic peptides, we have synthesized two

linear peptides,

D

-leucyl-

L

-prolyl-

L

-isoleucyl-

L

-valyl-

L

-alanyl-

b

-alanine (I) and

D

-leucyl-

L

-prolyl-L

-isoleucyl-

L

-valyl-

N

-methyl-

L

-alanyl-

b

-alanine (II), whose sequences were designed from

pro-todestruxin and desmethyldestruxin B by replacing

D

-leucic acid with

D

-leucine. We have analyzed

these flexible short polypeptides using 2D-NMR spectroscopy coupled with dynamic simulated

annealing to derive the solution conformations for these two linear peptides. Based on the derived

structures, it is found that the separation between

N

- and

C

-terminal residues of both linear peptides

are in a close distance favorable for the cyclization, in agreement with a high yield obtained in the

final cyclization reaction for these synthetic analogues of destruxins.

MATERIALS AND METHODS

Preparation of linear peptides. The peptides used for NMR determination in this work was synthesized by solid-phase peptide synthesis in HMP resin using an ABI automatic peptide synthesizer (Model 431A) essentially according to the previous report [12]. The Fmoc-amino acids were introduced using the manufacturer’s prepacked cartridges (1 mmol each) with a stepwise FastMoc protocol. The synthesized peptide was further purified by HPLC on a Vydac C18semi-preparation column. The purified peptides were characterized by mass spectroscopy (JEOL JMS-HX 110 Mass Spectrometer) and amino acid analysis (Beckman 6300 Amino Acid Analyzer).

Cyclization of linear peptides. To a solution of the linear peptide (50 mg; 0.085 mmol) in 120 ml of DMF at 0°C was added BOP (442 mg; 0.1 mmol) and solid sodium bicarbonate (30 mg; 0.357 mmol) [13,14]. The mixture was stirred at 0°C for 1 h and then at room temperature for further reaction. The progress of reaction was monitored by HPLC. The reaction was stopped by quick freezing and lyophilization and the cyclic peptide was isolated by HPLC. The purified cyclic peptide was also characterized by mass spectroscopy and amino acid analysis.

NMR spectroscopy. The NMR samples were made of ca. 15 mg in 0.5 ml DMSO-d6. All NMR experiments were performed on either Bruker AM-400, or AXL-400 or ARX-500 MHz spectrometer. Chemical shifts are referred to the solvent signal at 2.49 ppm. The assignments of the proton spectra of the two hexapeptides were made via the use of 1D proton and carbon spectra, DQF-COSY [15,16], HOHAHA [17], XH-COSY [18], NOESY [19] and ROESY [20] 2-D spectra. Spectra were recorded in the phase-sensitive mode with the time-proportion phase increments (TPPI) [19] method except XH-COSY, which was recorded in the magnitude mode. Typical two-dimensional spectra were recorded at 306 K with 512 t1increments, 2048 complex points (256 t1, 1024 for ROESY and NOESY, 80 t1, 2048 for XH-COSY). For the HOHAHA experiments, mixing time 80–200 ms was used. A mixing time of 150–500 ms was used for the NOESY and ROESY experiments. The ROESY experiment was performed by using a small flip angle (17°) in the pulsed spin-locked experiment to suppress chemical exchange [20]. After zero filling to a 1K × 1K or 2K × 2K matrix,p/2-shifted squared sine-bell functions were applied in both dimensions prior to Fourier transformation. The ROESY and NOESY spectra were processed by Felix program (version 2.05, Hare Research, Inc.). The temperature coefficients were determined over a temperature range of 27 to 67 °C at 5°C interval.

Computer-simulated modeling. The interproton distance information was derived by integrating the volume of the ROESY spectra’s cross peak similar to that described in the previous report [12]. The ROESY cross peak intensities of linear peptides I and II were integrated and used for the computation of the tertiary structure. The dihedral angles of Ile3 and Val4residues in both peptides were constrained within the limits [−180°, −80°] based on the coupling constants3J

HNa. All calculations were carried out on a Silicon Graphics, Iris 4D/35 and Iris Indigo Elan 4000 workstation. Structures were examined by the macromodel computer-modeling system “Insight II” from Biosym (version 2.2). Structures were calculated in two steps using NMRchitech program: DGII (distance geometry) and SA (simulated annealing) methodology. Both were executed with ROE constraints and dihedral angles. DGII includes smoothing, embedding and optimizing steps. Twenty structures obtained from DGII calculation were then used as starting points for the second-stage modeling based on the simulated annealing. From 20 random structures, 10 structures were selected based on the maximum distance violation of less than 0.5 Å, low total energy and the smallest root-mean-square deviation (RMSD) value.

RESULTS AND DISCUSSION

The characterization of conformational and dynamic properties of linear peptides in solution is

a challenging and important focus in current structural biology. NMR spectroscopy remains the

method of choice in this realm of research. During the process of the synthesis of destruxin

analogues, it was found that in contrast to most synthetic peptides a higher than 85% yield of

cyclization was obtained in this series of cyclodepsipeptides. The high yield of the ring closure was

probably due to a favorable conformation of the linear chain precursor. Therefore a systematic

analysis of two linear peptides,

D

-leucyl-

L

-prolyl-

L

-isoleucyl-

L

-valyl-

L

-alanyl-

b

-alanine (I) and

Vol. 219, No. 2, 1996 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

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D

-leucyl-

L

-prolyl-

L

-isoleucyl-

L

-valyl-

N

-methyl-

L

-alanyl-

b

-alanine (II), was carried out by

2D-NMR coupled with computer modeling to derive their solution conformation.

Preparation and Cyclization of Linear Peptides

The two linear peptides (I) and (II) were synthesized by automatic solid-phase peptide

synthe-sizer. The linear peptides were purified by HPLC and characterized by mass spectroscopy and

amino acid analysis. The cyclization of the two linear peptides was carried out in DMF solution

with low concentration to avoid dimerization or polymerization. The final reaction solution

ana-lyzed by HPLC showed almost only one product in the cyclization reaction; I

III, cyclo-(

D

-leucyl-

L

-prolyl-

L

-isoleucyl-

N

-methyl-

L

-valyl-

N

-methyl-

L

-alanyl-

b

-alanyl) and II

IV, cyclo-(

D

-leucyl-

L

-prolyl-

L

-isoleucyl-

L

-valyl-

N

-methyl-

L

-alanyl-

b

-alanyl). Both of these two cyclic peptides

showing longer retention times than their corresponding linear peptides in reverse-phase HPLC

were isolated by semi-preparative HPLC with over 85% yield, and their structures were confirmed

by mass spectroscopy and amino acid analysis. It is noteworthy that Lee and Izumiya [21] failed

to cyclize

D

-leucic acid-

L

-prolyl-

L

-isoleucyl-

L

-valyl-

L

-alanyl-

b

-alanine for the synthesis of

pro-todestruxin. Therefore the cyclization of linear peptides by amide-bond formation should be easier

than by ester-bond formation.

NMR Chemical-Shift Assignments for Linear Peptides

DMSO instead of DMF was used as solvent in NMR study for two reasons: (1) the solvent peaks

of DMF had more interference for the assignment of NMR spectra. (2) DMSO which possesses

similar polar property to DMF seems more suitable as a solvent for peptides.

The

1

H-NMR spectra of I and II were shown in Fig. 1. The

1

H chemical shift assignments for

I and II are relatively straightforward from HOHAHA, COSY and the conventional procedures of

sequence assignment. Judging from the spectra, there are two forms existed in these linear peptides

due to the presence of proline residue. The ratio of major and minor forms is about 3:1 on the basis

of integrated peak areas. From the ROESY spectra, it was found that strong correlation was

observed between

D

-Leu

1

a

H and

L

-Pro

2

d

H in the major form, indicating clearly the major form

as the trans Leu

1

-Pro

2

conformer. In contrast, cross-peak could be observed between

D

-Leu

1

a

H

and

L

-Pro

2

a

H in the minor form which should be the cis Leu

1

-Pro

2

conformer (Fig. 2). [22]. The

two conformers in the two linear peptides were also demonstrated in the two-dimensional

XH-COSY experiment. All

1

H and

13

C chemical shifts for two forms of both linear peptides are listed

in Table 1 and Table 2. There are two sets of

13

C signals of Pro

2

a

, Pro

2

b

, Pro

2

g

, Pro

2

d

and Leu

1

a

for I and II.

The

1

H-NMR spectra of cyclic peptides III and IV (data not shown) revealed only a single form

in these cyclic peptides. Strong correlation between

D

-Leu

1

a

H and

L

-Pro

2

d

H indicated that the

cyclic peptides were the trans Leu

1

-Pro

2

conformers.

Structure Calculation by Distance Geometry and Refinement by Simulated Annealing

The final structures of I and II were calculated from distance geometry and simulated annealing

based on ROESY distance constraints and dihedral angles. The minor forms of these linear peptides

had too few ROE distance constraints to be calculated. The superpositions of 10 structures of I and

II major forms are shown in Fig. 3. The conformational ensembles of I and II major forms show

good convergence and indeed provide qualitative evidence for folding. The root mean square

deviation (RMSD) values between all atom pairs among the ten structures of I and II major forms

are as follows: the average pairwise RMSD for all atoms is 1.661 ± 0.552 and 1.558 ± 0.645 Å for

I and II respectively whereas that for backbone atoms is 0.448 ± 0.368 and 0.296 ± 0.300 Å for

I and II respectively. The distances between

N

- and

C

-terminal residues in the trans forms of I and

Vol. 219, No. 2, 1996 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

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FIG. 1. H-NMR spectra of linear hexapeptides (A) peptide I and (B) peptide II. The NMR peaks corresponding to the minor forms of two peptides are labeled with prime (9 ) marks.

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II are 5.26 and 4.30 Å, respectively, which are short enough to facilitate the cyclization of I and

II in high yields.

Conformation of the Linear Hexapeptides in Relation to Cyclization

Small linear peptides are usually found to exist in random-coil structure and they exhibit a high

degree of conformational flexibility. However the high yields of cyclization obtained for the linear

peptides studied here would imply that the conformation of these linear peptides in organic solvent

does not exist in completely random-coil like states and possesses somewhat stable folded

struc-tures in order to facilitate the cyclization reaction. Based on the solution strucstruc-tures generated from

NMR data and computer-modeling, the major form of linear peptides with trans Leu

1

-Pro

2

con-former possesses a distinct

b

-turn in DMSO solution. However, the structure of minor species

could not be calculated owing to weaker NMR signals with overlapping peaks from those of major

species. Major species of linear peptides and cyclic peptides exist as conformers of trans Leu

1

-Pro

2

.

It is believed that cyclic peptides are produced directly from the cyclization of major trans forms

of linear peptides and the yield of cyclization increases by shifting gradually cis isomer (minor) to

trans (major) isomer with the equilibrium and subsequent conversion of both forms of linear

peptides to a cyclic peptide of trans form.

CONCLUSION

In most cyclization reactions of linear peptides, lower yields were observed [4]. In the synthesis

of two destruxin analogues reported here we have obtained high yields of cyclization for both linear

peptides I and II. The high yields of the ring closure in these two linear peptides probably arise

from a favorable conformation of the linear chain precursor [23]. By 2-D NMR coupled with

computer simulated annealing we have demonstrated qualitative evidence for the existence of

well-defined and folded conformation in the solution structures of these two supposedly flexible

and random-coil like short hexapeptides. The distances between

N

- and

C

-terminal residues in the

FIG. 2. Part of ROESY spectra (tm4 300 ms) for Peptide I which shows major (trans) and minor (cis) forms. Vol. 219, No. 2, 1996 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

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TABLE 1

The Chemical Shifts (ppm),3JNH-CH(Hz) and the Temperature Coefficients ofd(NH)(10−3ppm/K) of the Major Form and Minor Form£of Peptide I in DMSO-d6at 306K

1H chemical shifts Residue NH a-CH b-CH g-CH d-CH Others 3J NH-CH Dd(NH)/DT D-Leu1 7.78(−) 4.13(3.82) 1.55(1.41) 1.75(1.40) 0.88(0.79) 8.77 0.92(0.91) Pro2 4.37(4.74) 2.02(2.09) 1.89(1.67) 3.73 1.81 3.38(3.42) Ile3 8.06(8.13) 4.08(4.10) 1.73(−) 1.08(−) 0.80(−) g-CH30.81(0.81) 8.68(8.09) 4.53 1.48(−) Val4 7.60(−) 4.17(−) 1.95(1.95) 0.88(0.88) 8.86 4.14 Ala5 7.99(7.87) 4.20(−) 1.15(1.14) 7.36 4.94 b-Ala6 7.85(−) 2.34(−) 3.23(−) 13C chemical shifts Residue a-C b-C g-C d-C Others D-Leu1 49.71(49.36) 38.88(38.75) 23.40(−) 21.10, 23.02(21.05,23.02) Pro2 59.69(59.44) 29.42(29.30) 23.95(23.10) 46.59(47.05) Ile3 57.62(57.59) 36.05(−) 24.58(−) 11.00(−) g-CH315.45(15.32) Val4 57.21(−) 30.65(−) 17.84,19.11(17.93,−) Ala5 48.13(−) 18.22(18.27) b-Ala6 33.73(−) 34.72(−)

£chemical shifts of minor form in parentheses. Some assignment of the minor species are not listed owing to weak signal or overlap.

TABLE 2 The Chemical Shifts (ppm),3J

NH-CH(Hz) of Major Form and Minor Form

£of Peptide II in DMSO-d 6at 306K 1H chemical shifts Residue NH a-CH b-CH g-CH d-CH Others 3J NH-CH D-Leu1 8.12(8.20) 4.15(3.81) 1.49(1.58) 1.75(1.73) 0.89(0.89) 0.92(0.92) Pro2 4.38(4.74) 1.81 1.89(1.69) 3.40(3.42) 2.05(2.10) 3.73(−) Ile3 8.00(8.07) 4.10(−) 1.71(1.72) 1.08(−) 0.82(0.82) g-CH 30.79(0.79) 8.70 1.54(−) Val4 7.78(8.06) 4.52(4.54) 1.98(1.98) 0.84(0.85) 8.74 0.87(−) Me-Ala5 4.91(4.88) 1.16(1.23) NCH32.63(2.62) b-Ala6 7.67(7.87) 2.35(2.39) 3.22(3.32) 13C chemical shifts Residue a-C b-C g-C d-C Others D-Leu1 49.69(49.31) 38.88(38.75) 23.39(23.08) 21.08, 23.00(21.02, 23.10) Pro2 59.67(59.35) 29.41(29.35) 23.95(23.95) 46.59(46.67) Ile3 57.30(−) 36.31(36.10) 24.52(−) 11.02(11.10) g-CH315.34(15.21) Val4 53.56(53.78) 30.11(29.98) 17.97(18.21), 19.15(−) Me-Ala5 51.77(51.64) 14.21(15.11) NCH327.11(26.85) b-Ala6 33.72(33.64) 34.86(35.07)

£chemical shifts of minor form in parentheses. Some assignment of the minor species are not listed owing to weak signal or overlap.

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trans forms of I and II are found to be 5.26 and 4.30 Å, respectively, which are indeed close

enough to facilitate the cyclization of I and II in high yields.

ACKNOWLEDGMENTS

This work was supported by Academia Sinica and the National Science Council, Taipei, Taiwan. We also thank Mr. Fong-Ku Shi in M & Vactek Corporation, Taiwan for measuring 2-D ROESY spectra.

REFERENCES

1. Kessler, H. (1982) Angew. Chem. Int. Ed. Engl. 21, 512–523. 2. Kopple, K. D. (1972) J. Pharmaceutical Sci. 61, 1345–1356.

FIG. 3. Superposition of ten energy-minimized structures for the major (trans) forms of (A) peptide I and (B) peptide II. The dashed lines with numerical values indicate the distances between theN- andC-terminal residues of two linear

peptides.

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3. Nishino, N., Xu, M., Ueno, Y., Kumagai, H., Mihara, H., and Fujimoto, T. (1992) in Peptide Chemistry 1991 (A. Suzuki, Ed.), pp. 135–140, Protein Research Foundation, Osaka, Japan.

4. Bodanszky, M., and Bodanszky, A. (1984) in The Practice of Peptide Synthesis, pp. 207–210, Springer-Verlag, Berlin. 5. Bodanszky, M. (1984) in Principles of Peptide Synthesis, pp. 217–225, Springer-Verlag, Berlin.

6. Kodaira, Y. (1961) Agr. Biol. Chem. 25, 261–262.

7. Tamura, S., Kiyama, S., Kodaira, Y., and Higashikawa, S. (1964) Agr. Biol. Chem. 28, 137–138. 8. Suzuki, A., Kawakami, K., and Tamura, S. (1971) Agr. Biol. Chem. 35, 1641–1643.

9. Naganawa, H., Takita, T., Suzuki, A., Tamura, S., Lee, S., and Izumiya, N. (1976) Agr. Biol. Chem. 40, 2223–2229. 10. Vey, A., Quiot, J. -M., Vago, C., and Fargues, J. (1985) C.R. Acad. Sci. Paris 300, series III, 647–651.

11. Chen, H. C., Yeh, S. F., Ong, G. -T., Wu, S. -H., Sun, C. -M., and Chou, C. -K. (1995) J. Nat. Prod. 58, 527–531. 12. Liao, S. -Y., Ong, G. -T., Wang, K. -T., and Wu, S. -H. (1995) Biochim. Biophys. Acta 1252, 312–320.

13. Spatola, A. F., Anwer, M. K., and Rao, M. N. (1992) Int. J. Peptide Protein Res. 40, 322–332. 14. Fournier, A., Wang, C. -T., and Felix, A. M. (1988) Int. J. Peptide Protein Res. 31, 86–97. 15. Marion, D., and Wüthrich, K. (1983) Biochem. Biophys. Res. Commun. 113, 967–974.

16. Rance, M., Sørensen, O. W., Bodenhausen, G., Wagner, G., Ernst, R. R., and Wüthrich, K. (1983) Biochem. Biophys. Res. Commun. 117, 479–485.

17. Bax, A., and Davies, D. G. (1985) J. Magn. Reson. 65, 355–360. 18. Bax, A., and Morris, G. A. (1981) J. Magn. Reson. 42, 501–505.

19. Bodenhausen, G., Kogler, H., and Ernst, R. R. (1984) J. Magn. Reson. 58, 370–388.

20. Kessler, H., Griesinger, C., Kerssebaum, R., Wagner, K., and Ernst, R. R. (1987) J. Am. Chem. Soc. 109, 607–609. 21. Lee, S., and Izumiya, N. (1977) Int. J. Peptide Protein Res. 10, 206–218.

22. Wüthrich, K. (1986) in NMR of Protein and Nucleic Acids, pp. 123–125, John Wiley & Sons, New York. 23. Bodanszky, M., and Henes, J. B. (1975) Bioorg. Chem. 4, 212–218.

數據

FIG. 2. Part of ROESY spectra ( t m 4 300 ms) for Peptide I which shows major (trans) and minor (cis) forms.
FIG. 3. Superposition of ten energy-minimized structures for the major (trans) forms of (A) peptide I and (B) peptide II

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