1232
(30) (31) (32) (33)
at C(11) and its converse, derivatizationat C(11) to direct stereochemistry at C(15) had previously been reported, see ref I b , Id, and G. Bundy, F. Lincoln, N. Nelson, J. Pike, and W. Schneider, Ann. N.Y. Acad. Sci., 180, 76 (1971). C. Moussebois and J. Dale, J. Chem. SOC.C, 260 (1966); F. D. Gunstone and I. A. Ismail, Chem. Phys. Lipids, 1, 264 (1967). D. A. Van Dorp, Ann. N.Y. Acad. Sci. 180, 161 (1971). J. W. Hinman, 5th Annual Offshore Technology Conference, Houston, Texas, April 29-May 2, 1973, Paper No. OTC 1768; J. W.Hinman, S. R. Anderson, and M. Simon, Stud. Trop. Oceanogr., No. 12, 1 (1974). IR spectra were recorded with a Perkin-Elmer Model 221 IR spectrophotometer on Nujol mulls or as neat liquids between salt plates. The NMR spectra were run on a Varian A-60A spectrophotometer using deuteriochloroform solution with tetramethylsilane as internal standard. Mass
(34) (35) (36) (37) (38) (39)
spectra were recorded on an Atlas CH-4 instrument with ionization voltage of 70 eV or on a Model 9000 LKB gas chromatograph-mass spectrograph. UV spectra were recorded in 95% ethanol using a Carey Model 14 spectrophotometer. We are grateful to Dr. A. A. Forist and his associates for much of the analytical and spectral data and to J. H. Kinner, R. A. Morge, J. A. Woltersom, and J. M. Baldwin for technical assistance. We are indebted to Professor A. J. Weinheimer and associates for this material. M. Hamberg and B. Samuelsson, J. Biol. Chem., 241, 257 (1966). A hydrocarbon fraction, bp 60-71 OC. P. W. Ramwell, J. E. Shaw, G. B. Clarke, M. F. Grostic, D. G. Kaiser, and J. E Pike, Prog. Chem. Fats Other Lipids, 9, 1 (1968). Prepared as in "Inorganic Syntheses", Vol. 8, p 126. See ref 38, pp 125-130 for details.
Conformations of Proline DeLos F. DeTar* and Narender P. Luthra Contribution from the Department of Chemistry and Institute of Molecular Biophysics, The Florida State Uniuersity. Tallahassee, Florida 32306. Receiued May 24, I976
Abstract: The present study concerns the energies of the conformations of proline. We present results of an improved molecular mechanics calculation for ring conformations of Ac-Pro-OCH, and for the s-cis and s-trans conformations. Internal coordinates including all torsions have been calculated from crystal coordinates for more than 40 x-ray determinations to give a consistent set of data which define proline ring geometries. Results from the present work and from the many previous studies on proline derivatives by other workers permit the following definitive statements: (1) Although four parameters are theoretically necessary to define the conformational state of a five-membered ring having fixed bond lengths, in practice two parameters ordinarily suffice for the proline ring. (2) There are two broad energy minima (Figures 1 and 2) with a barrier high enough to rule out pseudorotation, but affording such flexibility of structure as to preclude the meaningful designation as envelope and chair or exo and endo. The most common conformational state approximates a range of C W r half chairs.' ( 3 ) There is as yet no really good method to get experimental measures of the conformational state of the proline ring in solution, although useful limits can often be established by treating N M R coupling constants by the Karplus relationships. (4) I3C NMR is especially useful for studying s-cis-s-trans equilibria of N-acylproline derivatives. Ratios range from about 15 to 40% s-cis for open chain derivatives. (5) The difference of the torsions x5 $J is not a constant but ranges from 54 to 80". This lack of constancy must be taken into account if proper conclusions are to be drawn from energy maps of proline-containing peptides.
-
'The importance of proline and of hydroxyproline in structural proteins, in enzymes, and in hormones is too well known to require comment. Structural features have been extensively investigated by x-ray crystallography, by ' H and I3C NMR, by various theoretical calculations, and by other methods such as IR and CD. One purpose of the present study is to bring together this extensive and scattered body of information so as to provide a definitive picture of the conformational properties of proline, particularly the energies of ring conformations and of s-cis and s-trans acyl groups. We have also performed new and sophisticated molecular mechanics calculations which lead to the energy profiles shown in Figures 1 and 2. Since previous calculations by other groups based on simplified force fields have given generally similar results, we conclude that the energy profiles are not very sensitive to the details of the force field and are therefore reasonably well defined. Although x-ray data are available for some three dozen proline rings, it is almost impossible to make a rational comparison of the x-ray data because some of it is incomplete and because every author uses a different numbering system. We have therefore recalculated all the internal coordinates of the proline skeletal atoms from crystal coordinates and present a unified and accurate tabular summary of the x-ray results. We have made a complete survey of NMR studies on proline derivatives and show in what respect these are relatable to the energy profiles. How to Describe Conformations of Five-Membered Rings. The biggest problem we faced in this study was to devise a convenient method for describing the conformational state of a five-membered ring. Even assuming that all bond lengths Journal of the American Chemical Society
remain constant, there remain four angles and torsions to be defined. Is it necessary to treat these independently, or is there some sound reason for supposing that, say, two would suffice? We were eventually able to show by molecular mechanics calculations that two parameters give an adequate definition for conformations having energies up to a few kilocalories above the minimum, but that more parameters are necessary to define conformations of high energy. We present our recommendations below. The starting point for defining conformations of fivemembered rings is cyclopentane, and the recommended conformational equations may be represented by the equati0n2-~
x, = a0 cos [ t + ( i - 1)4a/5]
i = 1, 2 , 3,4, 5 (1) In the earliest paper xI represented the vertical displacement of a given atom from the average lane.^,^ But x, can also represent a torsion; or it can represent certain other geometrical properties such as bond angle^.^ Whatever the meaning of x, t is the same quantity throughout, a phase angle that defines the distribution of puckering. The constant a0 is a puckering amplitude which defines the maximum value assumed by x and will necessarily depend on what quantity is being represented by x. For t = Oo, 36", 7 2 O , . . . , the ring conformation is of C2 symmetry ("half chair"). For t = 18, 54O, . . . , the conformation is of C, symmetry ("envelope"). For cyclopentane the conformational energy is independent oft, and in consequence the two normal ring vibrations are degenerate. The result is denoted as p s e u d ~ r o t a t i o n . As ~ ~rings ~ - ~ ~are ~ made less flexible by substitution, the energy becomes dependent on t and
/ 99:4 / February 16, 1977
1233 90
x2
Energy contour plot for ring conformations of s-trans-Ac-ProOCH3 defined by torsion x2 and dl (eq 2). $ has whatever value that gives an overall minimum. Steric energies were computed by molecular mechanics. There are two regions of minimum energy. For both the innermost contour is 0.5 kcal/mol above the global minimum, which is located at x 2 = -36, dl = - I ; the minimum at x 2 = 36, dl = -5 is 0.3 kcal/mol above the global minimum. Successive contours are at I , 1.5,2,2.5,and 3 kcal. The region between the two 2.5-kcal contours includes the saddle point of the pass, whose minimum height is 2.7 kcal. The diagonal lines are loci ofenvelope forms with the indicated atom up (+) or down (-) with respect to the average plane. The carbethoxyl group is up. The numbered squares show conformations for proline rings studied by x-ray crystallography; the data are from Table I . The points x are the s-cis conformations reported in Table IV. Figure 1.
eventually one or two conformations have lowest energies; the term pseudorotation becomes less applicable and eventually unsuitable.8 Incidentally, parallel treatments are applicable to rings of other s i ~ e s . ~ ~ ’ ~ There is no way both simple and rigorous to define the puckering geometry of a five-membered ring with lower symmetry than cyclopentane, but there are useful approximate definitions. Special aspects have been treated by Dunitz’ I and by Dunitz and W a ~ e r . ’Altona ~ , ~ ~and Sundaralingam6 applied eq 1 empirically to some 60 furanoside rings of ribose and deoxyribose for which x-ray data are available. For treating proline polymers Venkatachalam et al.I49l5define the puckering of the proline ring in terms of torsion angle xs (= 0 ) and a bending parameter r. Symmetry is utilized better by using torsion x2 and bending angle T , as is done in vibrational analysis of cyclopentanone and related compounds.16 Vibrational analyses of ring puckering for five-membered rings have been reported by many w o r k e r ~ . I ~ - ~ ~ It is often convenient to relate all ring torsions to one “master” ring torsion as shown in eq 2 . The relationships between eq l and 2 are summarized in eq 3, and for proline the appropriately indexed form of eq 1 is eq 4; X I = -0.809~2 x 3 = -0.809~2 x4
~5
+ +
d1 = 0 . 3 0 9 ~ 2 d2 = 0 . 3 0 9 ~ 2- d2
= a0 cos [ t
and t . It takes only two torsions to calculate dl and xz and hence all other torsions plus a0 and t . If more than two torsions are available, it is simple to perform averaging to get “best” values. Maximum simplicity of the relationships of eq 2 depends on proper choice of the master torsion angle, namely x2. Equations 1,2, and 4 are not exact; for most ranges of uo and t (or of x2 and dl) the steric energy due to bond angle deformation, torsion strain, and van der Waals forces becomes a minimum in accordance with a geometry defined by these equations. At extremes of geometry (or of energy) there can be appreciable departures. In practice eq 2 or 4 correlates torsion values to within about f2O and mostly within f 1O over ranges of conformations of usual interest. We note that eq 1 defined in terms of zi, displacement of the ith atom from the average ring plane, requires that Zzi = 0 and that in terms of torsions, xi, eq 1 also predicts that Zxi = 0; that is, the sum of the torsions is zero. Such relationships do not hold for larger rings.24
- dl
t = tan-’ [-dl/xz/sin ( 4 ~ / 5 ) ] a0 = xz/cos f dl = -a0 sin ( 4 ~ / 5 sin ) t d2 = dl sin ( 8 ~ / 5 ) / s i n(4a/5) xi
270
Polar plot of energy contours for s-trans-Ac-Pro-OCH3. Conformations for proline are defined by x,= no cos [ t + 4?r(i - 2)/5], eq 4. The puckering amplitude, ao, is radial, the phase angle t , which defines the distribution of puckering, is angular. Energy definitions are the same as for Figure 1. The diagonals are the loci of envelope forms with the specified envelope atom up (+) or down (-) with respect to the average plane. These are at t = 18”, 54O, 90°,. . . The carbethoxyl group is up. The pseudorotation path for cyclopentane is the dotted circle at no = 45; for cyclopentane all conformations represented by this circle have the minimum energy. Figure 2.
+ 4 ~ ( -i 2 ) / 5 ]
(2)
(3) (4)
the numerical constants in eq 2 are cosines of 4 ~ / and 5 8~/5. Equations 2 provide an especially convenient way to get at uo
Recalculation of X-Ray Data. The most definitive structural information for proline is based on the more than 20 x-ray studies of proline derivatives. However, we find that it is almost impossible to make effective use of the literature values because equivalent atoms are numbered differently in every paper and because many important internal coordinates are missing. We therefore have carried out a complete recalculation of all internal coordinates in a consistent way so as to present these valuable structural data in a readily usable form, Table I. In
DeTur, Luthra
/ Conformations of Proline
1234 Table I. Proline Bonds, Angles, Torsions, and Conformational Properties from Reported X-Ray Coordinatesa-d C-A 1.486 1.501 1.530 1.524 1.507 1.507 1.522 1.516 1.5.70 1.525 1.527 1.509 1.487 1.510 1.533 1.511 1.525 1.533 1.540 1.508 1.510 1.538 1.5~9 1.534 1.493 1.568 1.513 1.541 1.513 1.521
1 ACPRLAC 1 7 TOSPRHYHR 3 OIHYORPRO 4 ACTIN BPZ 5 CY-PR-LFU 6 CY-PR-GLV 7 ACTIN F2 e CURLPQ2 1 9 H-HYP-OH 1 0 ANTAU P8 11 TOSFRHY H 12 ANTAM P3 13 24PR-GPLG 1 4 CWBLPRP 2 15 BOPPPPBLS 16 LEUPRGL 2 17 BOPPPPBLl 1 8 CY-PPH 2 19 ANTAU P7 2 0 PNTAH P2 2 1 PO-PPP P2 22 CY-PPH P3 23 OL-FROHCL 24 AO-PPP F l 25 TOSPRHY P 26 BOPPPPRL3 27 BCPOPPBL2 2 8 CY-PPH 1 20 LEUFRGLYl 3 0 TOSPRHVPR 3 1 AC-PDO-hA 1.5JC 37 AO-PPP F3 1.531 33 ACTIN B F l 1.511 3 4 ACTIN P 1 1.492 35 L-PRO-OH 1.527 36 ACPRLlC 2 1.48E 37 TRIENPRCO 1 . 5 0 @ 31, ZZBGPLGFI 1.571 39 BOCPRO-OH 2.0904 0 Z2BGPLGF2 1.509
AVEQhGE S T O . DEV. O.F.
1.520 019
1.649 1.535 1.536 1.555 1 515. 1 514 1.562 1.538 1.526 1.568 1.534 1.555 1.549 1.514 1.561 1.496 1.551 1.561 1 575 1.562 1.537 1.545 1.543 1.553 1.551 1.470 1.596 1.537 1.496 1.535 1.530 1.525 1.488
1.567 1.522 1.401 1.554 1.622 1.529 1.544 1.540 -040
1. ? 3 2 .Pl?
8-6 1.5!€ 1.C5Z 1.517 1.502
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1.4€? 1.557 1.520
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1.544 1.520 1.415 1.575 1.41€
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1.407 i.4ea 1.510 1.51E 1.51F 1.55? 1.464 1.516 1.F28 1.517 1.405 1.50? 1.515 1.505 l.C?C 1.53C 1.5Cl 1.44E 1.5?€ 1.505 1.457 1.ClC
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1.484 1.517 1.572 1.513 1.506 1.545 I. 501 1.523 1.513 1.530 1.554 1.490 1.547 1.461 1.479 1.538 1.509 1.472 1.540 1.435 1.515 1.504 1.532 1.556 1.521 1.517 1.527 1.527 1.544 1.530 1.523 1.476 1.517 1.512 1.603
40
K-9 1.262 1.225 O.GOO+ 1.289
K-L 1.5CC 1.s21 O.OoF-
1.244
1.522 1.512 1.542 i.e48*
C-l-B 105.5 109.8 116.5 112.0 115.3 116.1 107.6 113.2 111.5 111.1 114.1 110.9
1.560 1.4?Q 1.508 1.505
1.848+
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1.236 1.272 1.2332 1.224 1.195 1 a240 1.222 1.212
I.EE@ 1.449 1.2FlZ 1.541 I .SEE 1.54e 1.574
a.000-
1.219Z 1.3451 1.227 1.203 1.213 1.272 1.442-
1.244 1.245 1.26R 1.263 0.0001.762 9.842. 1.262 1.23UZ 1.271
1.243 $023
2e
Journal of the American Chemical Society
28
/
99:4
114.7
112.0 110.6 113.3 109.? 111.5 106.9 109.3 111.8 1.5?3 110.1 113.0 o.oc01.?617 110.7 1.77t. 101.3 1.512 111.1 1.525 110.7 1.538 111.7 113.3 1.459 1.777108.6 1.4?C 111.5 1.LlC 111.1 1.524 112.0 i.5ze 110 - 9 0.0CO' 111.5 1.CCe 120.2 9.@42* 114.4 105.9 I.&€$
l.?JOZ 1.525 1.5z2 ,c 22 2p
1.499 1.547 1.407 1.531 1.428
1.470 1.459 1.524 1.511 1.458
1.472 1.476 1.536 1.507 1.471 1.483 1.516 1.465 1.493 1.498 1.463 1.492 1.454 1.468 1.476 1.481
1.465 1.516
1.484
1.487
032
o.ccc+
1.481 1.458
1.519
110
1.231 1.247 1.8750.0001.232 1.247 1.243 1.261
1.486 1.471 1.532 1.450
1.485 1.486 1.460 1.478 1.548
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1.SLC
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1.538 1.508 i.5ei
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40
39
N-K I PCPRLAC 1 1.331 2 TOSPRHYHR 1 3 2 1 3 DIHYOPPPO 7.3974 A C T I N BF2 1 . 2 0 2 5 CY-PR-LEU 1.342 6 CY-PD-GLY 1.321 F2 l . ? l l 7 ACTIN 8 CUBLPR' 1 2. 0471 0 H-HYP-Ot' 11.310+ 1 0 k N T I M PR 1.352 11 T O S P R H Y H 1.332 1 2 A N T A H F7 1.352 13 Z4BQ-cPLG 1.371 1 4 CUBLPRZ 2 2.0081.314 15 BOPPPPEI.4 1 6 LEUPRGL 2 1.338 1 7 BCPPPPBLl 1.3362 1 8 CY-PPH 2 1. ?38 1 9 C N T A H P7 1.??4 1.316 2 0 ANTAU P Z 1.328 2 1 AO-PPP P2 335 22 CY-PPH F3 I. 6.30123 DL-FPUHCL 1.3372 2 4 Ad-PPD F l 2 5 TOSPRHY P 1.59826 BOPFPPBLJ 1 . 2 9 6 27 BCFFPPBLZ 1.375 2 8 CY-PPH 1 1.746 29 LEUPRGLIl 1.339 3C TOSFQUYFR 1.647* 1.338 3 1 AC-PRO-Vb 37 Cr-PPP P3 1.?32 3' A C T I N B P l 1.302 34 A C T I N Pi 1.354 35 L-PRO-OF 3.23@* 3 6 CCPRL4C 2 1.331 37 TFIENPPCO 1.98OL 38 ZZE(GPLGF1 1.337 ' 9 BCCFRC-CH 1.3462 4 s Z?SCPLCD? 1.320 PVERPGF STO. O E V . O.F.
A-R
.028 40
R-A-N 91.1
102.7 103.7 103.2 103.2 102.7 101.8 106.7 105.0 104.0 103.8
102.7 101.4 104.2 102.4 103.7
103." 103.4 102.6 104.8 103.5
74.1. 1 1 0 -5
111.3 3.3 39
/ February
16, 1977
103.2
106.8 105.4 98.8 105.6 104.1 102.E
103.7 102.2 103.4
104.1 102.4 104.t 106 2
103.8 106 8 102.9 102.0 102.5 lF2.5 1.8
40
A- N 1.474 1.473
1.498 1.500 1.464 1.457 1.511 1.534 1.498 1.462 1.443 1.512 1.456 1.557 1.466 1.451 1.486 1.485 1.483 1.469 1.455 1.473 1.473 1.446 1.501 1.439 1.423 1.470 1.451 1.476 1.471 1.456 1.472
c-0 1.243E 1.2044 1.2381 1.267 1.228 1.233 1.257 1+2€8* 1 244A 1.217 1.1926 1 247 1.217 1.2684 1.216E 1.235 1.203 1.212 1.232 1 243 1e 2 4 5 1.213 1.2396 1.222 1.247 1.236 1.227 1.224 1.235 1.225 1.231
i.iazA 1.208
c-w 1.334 1.3261 1 242A 1.322 1.356 1.331 1.311 1.239' 1.242A 1.314 1.413h 1.356 1.365 1.310* 1.293E 1.313 1.375 1.335 1.352 1.352 1.332 1.346 1.325h 1.328 1.332 1.314 1.296 1.338 1.31: 1.329 1.317 1.33bA 1.325 1.338 1.239A 1.33k 1.293* 1.311 1.1754 1.4841
1.464
1.250 1.275A 1.243E 1.218' 1.216 2.6361.279A
1.476 .028 40
1.231 .OlB 25
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A-0-G
8-G-D 101.1 101.4 105.0 103.0 107.2 105.4 105.3 105.9 103.0 107.6 106.4 106.1 109.0 102.4 114.0 107.1 110.3 107.4 113.5 114.7 111.0 ia8.o 109.3 108.9
G-0-N 105.9 1c6.6
94.8
1c8.5
107.7 106.5 104.9
1e4.6
1.441
1.527 1.474 1.4n3 1.502 1.452
101.2 103.9 102.3 104.2 103.0 152.8 107.0 103.1 106.3 104.3 102.5; 107.1 108.3 107.6 106.4 lu7.8 107.1 105.7 106.8 156.2 lr14.6 104.7 100.8 102.0 115.4 106.0 101.7
104.5 105.8 198.2 104.7 103.5 11~2.5 1~0.3 100.8 108.4
103.4 103.2 104.1
104.5 154.8 2.0
40
25
105.3 104.7 101.j 103.1
104.3 loo.? 104.9 1c0.0 98.4
1FF.3 103.5
1t1.6
1 0 1 .tc 103.2
lei.? 103.2 101.7 100.0 104.1
104.1
[email protected] [email protected] 100.6 105.1
104.1.
1cj.6
102.3
1c3.6
104.2
102.8 102.9 10k.3 102.5 105.3 48.1 103.4 105.3
103.9 101.5 104.4 10 3.7
99.6 103.7 107.9 105.8 100.0 105.9 3.9 40
102.5 97.1
lG.3.1 2.3 40
-
1235 Tahlc 1 (conrirfued) 1 ACPRLAC 1 2 TOSPRHVuR 3 OIHYORPPO 4 ACTIN B F Z 5 CY-PQ-LEU 6 CY-PP-GLY 7 ACTIN P? 8 CUBLPRP 1 9 H-WYP-OH 1 0 ANTAH P8 11 TOSPRHY H 1 2 ANTAM P 3 1 3 Z(r9R-GPLG 14 CUBLPR2 2 15 BOPPPPEL4 It LC1JPRGL 2 1 7 EOPPPPBLl 1 8 CY-PDH 2 1 9 ANTAH P7 20 b N T P t l D Z 21 AO-PPP P2 2 2 CY-PPH P3 23 OL-FROHCL 2 4 IO-FPP F l 25 TOSFRHY P 26 aOPPPPPL3 27 PcpppPaLz 2h CY-OPH 1 2'1 LEUPRGLYI 3 p TOSPRHYPR ? l AC-PRO-FA 2 2 PO-PPP F3 3 3 ACTIN OF1 34 LCTIN P i 35 L-PRO-OH 36 i w R L a c 2 3 7 TDIENPRCO 3 n Z2BCPLGFl 39 BOCPRO-OH 40 ZZBGPLGP?
AVFPAGE STO. OEV. D.F.
I ACPRLAC 1 2 TOSPRHYHR
3 OlMYORPRO 4 ACTIN RP2
5 CY-PO-LFU 6 CV-PR-GLY 7 ACTTN P2 a CUBLPRZ i 9 H-HYP-OH 1 0 ANTAM P8 11 TOrPRHY H 1 2 ANTAH P j I ? ZCBR-GPLG 1 4 CUBLPR2 2 15 EOPPDPBL4 1 6 LEUPRGL 2 1 7 BODPPPBLl 1 8 CY-PoH 2 1 ; IINTAH P7 20 ANTPH F 2 2 1 IC-PPP P2 22 CY-PFH P3 2 3 OL-PROHCL 2 b AD-PPP P i 25 TOSPPHY P 26 BCPPPPELJ 27 BOPPPPBL2 2 8 CY-PPH 1 2 0 LEUPRGLYl 3n TOSPRHYPR 3 1 AC-PRO-PA 32 AO-PPP P3 33 A C T f N EPl 34 PCTIN P I 35 L-PRO-OH 36 ACPRLAC 2 37 TRIENPPCO 3 1 ZZEGPLGFI 39 BOCPRO-OH 4C Z2BGPLCP2
AUERAGF S T D . OEV.
0.F
-
0-N-i 112.2 110.5 107.3 111.3 112.5 112.2 111.1
106.2 109.1 112.9 llE.3 11?.9 L13.j 103.3 113.5 113.3 115.4 108.3 114.9
113.9 113.1 111.6 104.6 113. E 111.1
112.4 113.2 111.1 11z.3 112.5 112.2
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121.4 2.9 28
113.2 118.3
124.8
121.1'
'
106. 82.5' 126.4 115.1 125.1 121.6 104.3' 118.6 120.6 123 - 6 2 127.5
90.0'
120.7 124.0 124.0 121.6 115.6' 39.34 120.6 125.0 120.9 123.9 114.5' 127.9 126.1 120.32 121.6 126.6 125.0 128.3 119.4 45.0' 120.92 120 . 9 125.5 127 0 118.3 i26. I 121.3' 125.5 127.1 121.7
120.9 122.1 123.4 119.6 93.4' 90.0' 124.3 113.3 120.0 119.7 9 5 .E122.2 122.5 124.32 121.3 120.3 118.6 120.3 120.9 90.0' 124.92
116.5 2.2 25
122.4 3.4 28
124.1 3.0
C-A-N 115.2 109.7 112.8 112.5 110.9 111.1 112 -6 107.3 110.7 108.4 117.8 106.9 116.7' 104.3 113.9 111.2
h-A-E-b
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B-G-0- N -35.3 -30.9 -23.1 -30 1 -25.1
G-0-N-A 9.8 12.0 -1.6 11.1
111.4 108.6 1 1 0 .l 112.0 110.3 109.5 111.3 111.3 109 e 5 109.6 110 .l
108.4 111.2 i l l .4 114.3 104.9 113.2 113.3 106.4 115.2 110.2 113.2 1 5 3 .7* 110.2 111.1
2.7 39
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14.0 16.3 16.1 14.7 8.0 8.0 -6.5 -19.7 -21.8 -23.1 -27 45 -28.6 -28 e9 -31 0 -31 -4 -31.4 -32.4 -36.2 -37.5 - 4 1 e6 -39.1
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3Q.9 33.6 35.6 -42.7 -19.5 24.0 27.2 -3.0 27.2
40
N-K-P 121.0 121.1
1ll.U'
121.5 3.0 i5
L-u-0 121.4 123.2 90.0' 117.9 124.2 122.8 119.9 175.6' 90.0' 120.5 133.5 121.1 121.7 175.6' 121.5 110.9 125.82 120.4 121.7 117.3 121.5 120.6 90.0' 125.32 105.7' 121.4 120.7 121.6 118.9 106.3' 122.9 120.5 117.7 119.6 90.0' 121.4 0-
114.0
0-N-K 125.9 129.6
121.9 2.3 25
111.6 3.0 40
.
117.8A 118.4A 120.2
A-N-K 120.7 119.9 11.3' 125.7 123.5 122.2
54.7' 110.9A
119.4A 121-4E
114.0
u
115.7 115.3' ii7.en 122.2 1 2 ? ,211 12E - 4 122.0 1 1 4 .E+ 122.SE 121.4 120.7
A-C-H 117 .OE
116.6A 113.0 112.1A 113.0 116.0 122.7* 113.8E 115 - 3 117.1 118.5 li5.1 118.9 118 .o 117.7 112.9A 118.2 111.2 116.2 118.6 118.2 115.3 115.7 117.9 110.7A 117.9 118.1 121.5A 117.OL 115.4' 115 -6 87.2' 172.3A
123.0' 125.3 57.0' 65 . l A
122.8 125.32 122.0
Q-L-0 12I.tE 122.21 115.?A 117.1 122.8 122.5
119.4
119.1' 125.9 125.3' 125.7 121.22 121.0
28
4.4 3.2 6.9 34.9 23.1 23.7 28.0 22.2 5.9 45.6 2.6 21.0 6.9 35.6 3.1 -8.1 -1.9 11.6 18.4 -2.7 -28.9 -9.7 -3.9 5.0 -8.2 -20.0 -14.2
-12.8 -11.7 -10.8 -12.4 -20.8 35.2 3.5 -4.0 -6.6 5.0 17.1 40
N-K-L 117.6 115.7 90.04 121.0 113.9 113.9 120 e 4 95.8'
au .o+
115.1 111.2 l i d-9 118.5 85 6 4 llb.2 118.5 lC9.92 118.2 117.9 123.1 118.2 118.5 40.0' 109.72 lC9.8' 118.6 117.1 117.7 118.5 108.8' 117.0 118.0 121.4 118.7 90.0' 117.6 79.9' i17.7 110.52 118.6
118.8'
120.0 121.9 120.7 122.5 104.3' 120.1 121.5 120.9 121.7 90.0+ 121.0 79.9' 119.5 124.12 119.4 120.7 1.9 28 0-N-A-8 18.2 12.6 25.3 11.5 17.0 16.9 12.2 -15.1 -3.0 -5.4 -9.7 -7.5 5.8 -33.5 6.2 -11.1 1.5 -30.4 1.3 -1 e 4 -9.7
117.8 2.4 78
8- A -C -0
9.2 -7.2 -15.4 -24.2 -11.1 .3 -7.7 -10.3 -15.3 -14.3 -13.7 -3.9 -14.8 12.T -17.0 -14.6
-44.lE 68.0A 131.1A 73.0 -28.1 -25.4 77.9 71.P 113.4A 73.8 78.7A 68.7 -c3.0 02.2' -1C0.9E 94.4 e0.2 25.3 P2.1 85.0 72.8 29.2 -1Jl.lA $9.1 98.6 e5.7 99.6 18.5 94.4 e? .2 -78.0 97.3A 84.2 c5.4 108.6A -75.7E -40.14 -92.2 122.8' -08.2A
-5.4 14.7 40
47.5 61.9 25
-24.9 -33.7
-14.3
DeTar, Luthra
/
Conformations of Proline
1236 Table I (continued) I ACPPLAC 1 2 TOSPRHYHR 3 OIHYORPRO 4 ACTIN BF2 5 CY-PQ-LEU C CY-PR-CLY 7 ACTIN PZ 8 CUBLOR2 1 ? H-HYP-OH 10 ANTAM D P 11 TOSPRHY H 1 2 A N T A W P3 1 3 Z4PR-GPLG 1 4 CUBLPR2 2 1 5 BGPPPPBL4 1 6 LEUPRGL 2 17 BOPPPPBLI 18 LY-PPH 2 1 9 A N T A M P7 2 0 A N T A W P2 2 1 AO-PPP P2 22 CY-PPH P3 23 OL-FROHCL 2 4 PO-PPP P l 25 TOSPRHY P 26 BOOPPPPL3 27 BOPPPPBLZ 2 8 CY-PPH 1 29 LEUPRGLYl 7 F TOSPRHYPR 3 1 AC-PRO-HA 32 BG-PPP F3 3 3 ACTIN B F l 3 4 ACTIN Pi 3 5 L-DQO-OW 36 ACPQLAC 2 37 TPIENPRCO 3e ZZBGPLGCI 39 BOCPRO-OH 4C ZZRGPLGFE
AVERllGE S T O . OEV. O.F.
E-A-C-M 84.1E -109.24 -51.46 -103.2 150.4 155.5 -100.5 -lJb.l* -64.76 -99.1 -101.4A -110.0 85.0
N-4-P-n
-86.6.
-165.7' 144.5E -22.0 -33.0
7€.OE -81.7 -44.3 -155.0
-100.3 -93.9 -106.6
-150.4 47-41 -88.1
-99.3 -91.4 -80.8 -164.2 -81.7 -91.0 101.0 -79.OA
-94.8 -91.7 -74.6A 102.5E 141.6' q5.4
-88
.a
-28.5 -30.7 -41 -8 -83.7 -10.9A -27.6 -5.1 -30 - 6 -15 $0 -93.9 -22.0 -24 e 6 165.2 -17.4A -31 -0 -31.9 -6.9A 158.9E -160.5' 155.8
-60.0
-23.4
93.2 25 L -K-N
OEV.
-42.6 148.6
159.26
-A
2 TOSPRHYHQ 175.5 7 OIHYORPRO 90.0' 4 ACTIN BP2 12.7 5 CY-PR-LEU 6.2 6 CY-PR-GlY 7.7 7 ACTIN P2 12.7 8 CUBLPRZ 1 lO.l* 9 h-HYP-OH 90.0' 1 0 ANTAW P8 -3.7 11 TLSPRHY H 170.6 12 ANTAH P3 -11.5 1 3 Z4BR-bPLG -174.4 14 CUBLPRZ 2 26.3' 1 5 BOPPPPBLS 1 7 9 . ~ 1 6 LEUPQGL 2 175.2 17 BOPPPPBLI -1.OZ 1 8 CY-PPH 2 19.2 19 ANTAM P7 -177.0 ? C ANTAW P2 177.3 2 1 PO-PPP P2 171.9 2 2 CY-POW F 3 .4 23 OL-PROHCL 90.0. 2 b AO-PPP PI -1n.s~ 25 T O S P R H Y P - 7 6 . t ' 26 BOPPPPBL3 176.3 27 BOPPPPBLE 188.6 2 8 CY-PPH 1 1.4 29 LEUPRGLVl 175.2 3 0 TOSPRHYPR -77.7' 3 1 AC-PRO-MA -177.0 32 GO-PPP P3 -179.0 33 ACTTN B p i 18.0 3 4 ACTIN P 1 20.3 35 L-PRO-OH 90.0' 3h ALPQLBC 2 -171.7 37 TRIENPWO 101.9' 38 ZZBGPLGPl -168.7 3 9 BOCPRO-OH -5.62 40 ZZBGPLGFZ 177.8 STO. O.F.
11 e31 -42 - 7 -144.8 -142.2 -33.5 -171.2' -7.2A -39.9 -43.5A
175.7' -3l.OA
1 ACPRLAC 1 -171.7
AVERAGF
158.9C -44.1h
21.9 137." 28
38.0'
76.7 25 L-K- N-0 -5 .a -4.3 90.0' 174.0 -176 - 7 178.6 172.R 128.1' 90.0. 172.2 12.8 171.9 -4.0 138.5' -3.7 - 3 .e 172.62 178.7 -2.0
-9.9 -3.4
172 .8 9 0 'O. -174.12 63.1' 2 -3 -3.5 167.0 -3.8 66.9'
N-b-C-M
-2E.CE 138.7A -171.?A 141.1 33.7 38.7 i4e.4 llJ4'
178 .?A 147.2 13€.4A i3c.e - 3 ? .4 25-58 -3E.7E 161.9 152.F 91.7 14C.F
15 0
L.
13.?e'? 9t.e l87.CA 155.1 157.0 152.2 164. t 8t.5 161.9 157.2 -15.9 1Et.lA 15C.O 151.0 1 7 0 .@A -22.FE 2 1 2. -2C.7 9o.e. -14 2 .8A
1 1 7.9 b?.t 25
K -N -A -C -62.0 -50.5 -102.7' -64.9 -41.6 -44.3 -71.0 -12.~9 146.84 -70.9 -42.2 -67.5 -57.6 -31.0. -57.0 -68.2 -67.42 -110.2 -69.6 -69 -4 -66.0 -94.8 1?5.8* -59.92 -102.19 -62.2 -69 e 9 -99.5 -68.2 -96.2-76.3 -73.2
b.4 -9.4 -175.5
169 - 7
148.9 28
9C.C'
90.0'
172.EZ 161.9*
148.1
n1.0
PADN
.si1 -328 R 637 ~ 3 0 3 ,432R .47c R 324 .384R -.078 -.143R 251F -.199R ,153
-.
e809 .165
-.281 .OUR -.769 -036 0 3R -.25t -.633R -819 -.369R -245 -.177 -.412 -.6141i 280 ,008
-.
-8.4
4.5
8.92 -58.6" -178.1 -178.4 -12.6 -179 6 -46.2. 172.9
-1.3
1.7 -162.t
lf9.4 .9
-.263
-16f.t
-1.3 90.0' 176.0 -22.2' 179.6 -72 -178 .U
-.374
-178.4 -178.4 90 .Os -5.0
-22.2' -1.7 -179.82 2e 9 29.0 107.6 28
-4.0
-E..? -178.2 - a t
16 C 24
9C.V 9.?
101.e. 12.7 174.42
-T.l
42.1 134.5
-4P.2 1OE.P 2e
Journal of the American Chemical Society
/
'
-69 $ 2 16.3 28
178.8 -6.9 179.1 -37.3' 179.6 -179.6 -4.02 -3.9 174.7 177.2 179.3 -7.5
e.?
142.3
148.0
-133.0 164.5 - 1 5 0 4' -178.8 168 e 4 Z 170.2
-1r1.3
-145.5' 2.t -.E -177.tZ -16?.4 -.4
130.44
174 3 -165.6 -169.0 174 .l ioe.c+ 26.3' 170.8 -169.5 175.7 177 1 86.5' -176.4 169.7 175.52 131.2 178 9 172.1 174.3 148.0 -60.4' -179.02 152.5' 178.1 171.4
-91.1 -14 *Ow -62.0 -2 5 6' -65.0 -1is.34 -7 2 2
-8.4
[email protected]'
-167 - 2
-39.6
-47.6' 90.09
17T.e -2?.4 16C.t
-e
-173.4
162.3 167.7 149.6
0-K-N-0 176.0 177.4 90.0' -9.6 3.7 -1.3
Q-K-L-A C.? -2.7 9C.C' -17C.e -17t.Z -17P.t -1bE.5 -1BS.S'
1
K-N-I
28
99:4
-.
-19.5. -152.6
-1l2. 9 -168.8 -155.7 -b3.3' -27.04 -152.7 -174.4 -160.9 -1€5.1 -67.2' -174.4 -159.9 -167.2Z -127.4 -172.0 -175.3 173.6 -162.0 1 7 6 74 112.42 -170.1' 164.8 168.6
-163.1 170.9 -166 $1' 176. 3 169.3 -177.0 -174.3 82.7' 171 6 160 3-164.2 170.82 168.8 -6n.4 154.2
28 G-ION -.242 -.296R e041 -.292 -.114R -.082R
-.la0 .845R
-.57? -.598R -.711* -.574R -.I49 1.081 -.866
-.515 -.181R -.a55 -.079 -055 .047 -.296R -456
.071R a714 ,252 .io0 -.128R ,212 ,512 -3669
-.19RR
-.384 -.34bli -.a92
-.
381 R
,348 -.438R -.3FO ,023 ,405 25
/ February
K-N-D-G -157.9 -168 I
.330 ,289 -277 .317R e562 846Q -.a89 ,103R -179
-.
.082
.422
16, 1977
25
C-A-E-G -157.9 -148.0 -163.7 -151.7 -152.6 -153.8 -146.8 107.6 -138.3 -131.8 -143.1 -124.9 -142.9 120.6 -135.7 -124.1 -128.4 -103.5 -121.1 -115.6 -101.7 -89.1 157.8 -95.6 -98.4 -96.8 -90.1 -82.2 -94.7 -97.2 -96.3 -89.0 -87.9 -90.5 -82.0 -100.8
-133.5 -142.5 -122.1' -85.8 -98.7 71 e 2 39 C-AON 1.036 1.092R -658 1.WbO .88bR
-8341 1. I 2 0 .991R 1.269 1.333R 1.197R 1.3621 1.001 .709 1.139 1.321 1.246A
1.451 1.313 1.245 1.331 1.449R .543 1.37bR 1.283 1.364
1.383 1.4589 1.321 1.272 1.276R 1.583 1.338 1.313 l.bl3R 1.031 1.330R 1.160 .812R 1.380 1.175 .239 25
C-L-N-0 129.6 129.4 152.2 1?2.4 1 4 1- 0 143.6 127.2 -136.8 117 - 5
112.9 117.6 1t9.3 131.1 -151.0 125.6 ill.0 118.6 88 .l
114.8 117.0 110.0 92.4 -157 e 5 1c5.7 114.6 112.6 103.3 94.1 111.0 116.1 113.7 108.8 105.5 1Qb.b 105.3 129.6 110.0 126.6
€1.2' 103.0 96.0 72 .8 59
1237 Table I (continued) K-NAC 1 ACPRLAC 1
2 TOSPRHYHR 3 DIHYDRPRO 4 E C T I N AF2 5 CY-FQ-LEU t CY-PR-GLY 7 ACTIN F2 8 CUBLPRP 1 9 H-HYP-OW 10 ANTAM PB
11 TOSFRHY 12 13 14 15 16 17 18 19 2F 31
22 23 24 25 26 27 28 29 30 31 ?2
37 54 35 36
37 38 39 40
H
LNTAH P 3 24PR-bPLG CUSLPRP 2 BOPPPPBL4 LEUPRGL 2 BOPPPPSLl CY-PPH 2 ANTAM P7 PNTAM P 2 IO-PPP F 2 CY-PPH P3 OL-PROHCL PO-PPP P i TOSPRHV P BOfPPPBL3 BOfYQPBLZ CY-PPH 1 LEUPRGLVI TOSPRHYFR AC-PRO-PA PO-PPP P ? ACTIN P e l ACTIN P i L-PRO-OH ACPRLAC 2 TRIENPRCO ZZRCDLdFl BOrPQO-OH ZZRGPLGPE
-1.01
.89 -7.14 -.a6 .74 .78
-1.02
B-NAC 1.52
-1.34 1.19 1.30 -1.22 -1.21 1.39
.44
1.25
-6.14 -1.13 .81 -1.n2
-1.27 1.34 -1.19 1.35 1.24 1.30
-.9Q
1.04
-.97 -1.07 -1.03 1.0G
-1.09 -1.06 -1.07
-1.04 -.27 -.96
1.33
1 e23 1.35
-1.33 1.41 1.33 1.30 1.34 1.23
1.30
1.40
-1.40
-.“7
1.23 1.36 1.32 1.23 -1 - 3 5 -1.27
-1.15 -1.03 -1.07 1.46 1.11 -1 39
G-NhC 1.60 -1.C6 1.10 1.57 -1 .?O -1.26 1 .I2 2.05 -1.70 1.78 -1.51 I.a0 1.59 1.03 1.77 1 .e5 1.90 - 2 -13 2.c3 2.02
2.10 2 -25 1.27 2.18 -5.41 2.13 2 -23 2.28 2.18 -2.23 -5.19
1.29
2 .i?
.
-1 - 2 5 -1 -30 1.28 .99 -1.22
22 -- 22z..-23
1.45
i.eo
-1.131
1.46
-1.33
1.33
1.52 2.52
1.?8
1.10
-.?E
-1.31 e2 -1.15
25
0-NAC
1.06 -1.06 68 1.00 -.86
-.79 1.12 1.02 -1.25 1.30 -1.14 1.27 1.00 .72 1.13 1.25 1.16 -1.40 1.2E
1.23 1.2’1 1.38 -56 1.29
-1.27 1.28 1.31 1.39 1.25 -1.22 -1 - 2 5 1.30
-1.31 -1.34 1.37
2.c2
1.06
-;.E7
-1.35 1.07 1.19 1.38
GAMMA 41.69 35.28 31.66 34.30 31.84 31.02 29.63 -38.79 33.07 33.29 34.5e
26.81 19.44
-30.11 14.99 19.33 14.77
17.41 7.81
-9019 -17.14 -15.02 14.25 -24.6e -29.34 -27.75 -28.17 -24.7’3 -26.41 -32.17 -34.36 -35.25 -37.73 -36 - 7 4 -38.34 -40.70 38.34 23.9 t -30.59 -34.87
DI 2.18 .22 8.16 -19 3.57 4.53 1.69 -15 6 5 -7.84 -8.88 -11.16 -8.82 12 -24.17 .82 -9.54 -1.67 -19.98 66 29 -2.04 -10.83 -15.86 -3.13 10.54 .72 -3 1 2 -8.77 -1.00 5.77 1.95
-.
-.
.78
-1.12 -.Yl
-.19 4.08
-15.50 2.41 -3.78 -2.34
A0 45.93 38.56 40.90 37.03 36.48 36.43 33.46 42.54 34.71 34.74 36.18 28.79 20.91 45.31 16.40 22.89 15.02 34.93 8.08
6.55 19.36 28.55 35.49 23.0C 33.84 28 9 4 31.47 34.74 31.43 33.87 36.33 37.54 41.66 39.1? 4 0 -96
42.76 42.01 26.90 35.58 38-87
T
-4.64 -.55 -19.84
-.49 -9.58 -12.20 -4.92 38.15 22.61 25.78 31.68
31.43 .56 65 1 7 -4.85 45.17
10.94 76 - 7 3 7.97 184.33 lt9.97 139.80
170 - 5 1 lE9.04 212.14 182.44
170.29 154.56 176.69 146.84
135.23 lP2aC3
177.38 177.48 179.54 1e9.34 ‘9.14 -8.78 169.56 173.99
aColumn headers (see also the figures): C (Cl), A (C,% B (C,P),G (C,’Y), D (CIS), N (NJ, 0 (01), M (N’), K (Co\, Q (OJ, L (Goa), where subscript 1 designates proline, 0 designates preceding acyl residue, and 2 designates succeeding residue. Bonds are denoted by C-A (Cl--Cla), angles by C-A-B (C,-C,a-C,P), torsions by N- A--B -G (N,-Cla--C,P-CI’Y); B-ADN signifies distance from C,P t o plane ADN (CIa-Cl6N,) and R means that origin and C (C,) are on same side of the plane; for GAMMA,D,,Ao,and I’see footnotes b and c. Symbols for comAC-PRO-MA, Ac-Pro-NHCH,, Matsuzaki pounds:’ ACPRLAC, Ac-Pro-Lactyl-NHCH, (1 for “exo” C’Y, 2 for “endo” CY), C..Lecomte et and Iitaka;28ACTIN, actinomycin, bis peptide sequences (L-Thr-D-Val-L-Pro-Sar-L-MeVal lactone), P1 and P2 are two prolines, B indicates crystal data from the 7-Br derivative, Jain and S0be11;’~ANTAM PJ, sodium complex of antamanide analogue, c(Va1-Pro-Pro-Phe-Phe-Val-ProPro-Phe-Phe), where J is number of Pro residue, AO-PPP, amyloxycarbonyl-L-Pro-L-Pro-L-Pro-OH, 1,2,3-Pro unit counting from amino end, G . Kartha et BOPPPPBL, Boc-L-Pro-L.-Pro-L-Pro-1-Pro-OBzl, 1,2,3,4-Prounit counting from amino end, M a t ~ u z a k i ; ~ ’ ~ BOCPRO-OH, t-Boc-Pro-OH, coordinates reported for C, the carboxyl carbon, are in error, Benedetti et al.;”’ CUBLPR, bis(N-benzy1-Lprolinato)copper(2+), Aleksandrov et CY-PPH, c(L-Pro-1.-Pro-L-Hyp) (1 is Pro, 2 is Pro or Hyp, 3 is Hyp), Kartha and am bad^;^^ CYPR-GLY, c(L-Pro-L-Gly), Von Dreele;35CY-PK-LEU, c(L-Pro-L-Leu), Karle;36DIHYDRPRO, 2,3-cis-3,4-rrarzs-3,4-dihydroxy-~-proline, K ~ l e ; DL-PROHCL, ’~ dl-proline hydrochloride, Mitsui et al.;,” H-HY P-OH, K o e t ~ l eLEUPRGL, ;~~ H-L-Leu-L-Pro-Gly-OH (1 is Cy: and 2 is C,”), Leung and Marsh;40L-PRO-OH, L-proline, Kayushina and Vainsl~tein;~’ TOSPRHY H, Tos-1-Pro-L-Hyp-OH, R indicates revised calculation of the Fridrichsons and Mathieson data:’ Sabesan and V e n k a t e ~ a n ; ~TRIENPRCO, ’~ trietliylene tetraamineprolinatocobalt(II1) cation, Freeman et al.;43bZZBGPLGR, Z(o-Br)Gly-L-Pro-L-LeuGly-Pro-OH with H,O and ethyl acetate of crystallization, only a rather poor crystal was available (1 is internal Pro, 2 is terminal), Ueki et Z4BRGPLG, Z@-Br)-Gly-L-Pro-L-Leu-Gly-OH, Ueki et al.44bbFlags: A, acid; E, ester; Z, alkoxycarbonyl, *, exceptional or nonexistent atom; entries marked with * are t o be disregarded. R, unimportant, but means that C (C,) and origin of crystal coordinates are on same side of the ADN (C,a--C,s-N,) plane. CK-NAC, B--NAC, G-NAC, D-NAC are distances of C,, C,P, C,r, and CIS from the plane defined by N , , C,“, C,. Distances with same sign are on same side of plane. GAMMA is equivalent to or identical with the r of Venkatachalam et al.,I5and follows their sign convention: negative for C,’Y on same side of reference plane as C,. D ,is defined in eq 2 and 3. For proline xi = a , cos [r + 4n(i - 2)/5] ; eq 4 . dAverages are based on all unflagged entries in a given column. There are some minor duplications, but these have negligible effect on the averages. The most probable average values for B-G and G-D are 1.53-1.54. The reported short distances are an experimental artifact. See text.
most cases our numbers agree closely with the literature values where available, but we found a few typographical discrepancies. In all cases of discrepancy we rechecked our input data against the crystal coordinates. Previous summaries of the x-ray data have treated relatively few ~ t r u c t u r e sFor . ~ ~further ~ ~ ~ data see Table VI11 and supplementary material. The following points are of importance in evaluating proline x-ray data: the mobility of CP and Cy and to a lesser extent of C6even in the crystal lattice has often caused difficulties in defining ring geometries. Examples are entries 1 and 36, which represent two different calculations for Ac-Pro-lactamide, and entries 16 and 29, which are two treatments of the data for H-Leu-Pro-Gly-OH. The reported geometries must therefore be treated with some caution: the sorts of errors that may be present can be seen by comparing entries 2 and 30, revised
calculations for Tos-Pro-Hyp-OH, with the original values, entries 11 and 25. For large molecules the level of uncertainty can be estimated by comparing entries 17 and 34 for actinomycin with entries 4 and 33 for the isomorphous 7-bromoactinomycin. But perhaps the most significant fact to emerge is that proline geometries are relatively constant whether present in salts, metal derivatives, or peptides, or whether the N-acyl group is s-cis or s-trans. We next consider specific structural elements, first bond distances. Ring bond distances A-B (Ca-Ca),B-G (CB-CY), and G-D (CY-C*) may have been systematically underestimated. Electron diffraction results for cyclopentane show a C-C distance of 1.546 A.4There are no obvious reasons why proline C-C bonds should depart appreciably from 1.53 to 1.54. Libration corrections on such compounds as caprylolactam raise apparent short C-C bond lengths to normal vaDeTar, Luthra
/ Conformations of Proline
1238 Robiette defines various measures of interatomic distances and discusses the effect of bending vibrations on apparent distances.45b Ring bond angles tend to average 104' except for D-N-A (C6-N-C"), which averages 113' (1 12.9 f 1.7', 33 df, after deleting the seven salts and complexes). The 113' value is reasonable, since depression of the normal value of 1 15- 120' for the C-N-C amide angle (as estimated from N,N-dimethylamides) to 113' parallels the decrease of a normal C-C-C angle (109') to 104' (Aubry et a1.,46,47 Kitano et a1.,48 Gobillon et al.49). Both angle reductions result from ring puckering. We report values of dl ( D I ) which along with x2 (A-BC-D) and eq 2 reproduce ring torsions x I (N-A-B-G), x3 (B-G-D-N), x 4 (G-D-N-A), and x5 (D-N-A-B). For the 160 torsions in Table I the standard deviation of the values calculated from x2 and dl is about 0.6'. We also report values of a0 (AO) and t (T) for use in eq 4. These, of course, reproduce the data equally well. As for planarity of the peptide group, the angle w is the average of L-K-N-A (CO"-CO-NI-CI") and Q-K-N-D ( O O - C O - N I - C ~(or ~ ) equivalently the average of L-K-N-D and Q-K-N-A minus 180). Angles near 180' must both be expressed as positive angles before averaging. The s-trans form has an angle near 180". Torsions @ (K-N-A-C, CO-N~-CI"-CI)and J, (N-AC-M, N I - C ~ " - C I - N ~largely ) determine chain folding, but angles N-K-L (NI-CO-CO~), A-N-K (CI"-NI-CO),C-A-N (CI-CIOI-NI),and A-C-M ( C I * - C I - N ~ are ) also involved; the 3' variability may be significant in some cases. For the seven s-trans derivatives = -66.1 (46)' with a range of -57 to -76' and (x5 = 62.5 (f7.4)' with a range from 55 to 80'. For the 11 s-cis derivatives = -75.1 (f23)' with a range of -42 to -1 10' and (XS= 69.3 ( f 7 . 8 ) with a range of 59 to 80'. These values lend little support to the hope that @ could be predicted sufficiently closely, given the value of x5, or vice versa. In Table I we also report other derived values considered to be of interest. One example is the distance between C I and ~ Cly and a reference plane defined by C I ~ - N I - C I " . ~An*~~ other is y; we have defined y as the angle between three points: C17, the midpoint of the line joining ClO and C16, and the midpoint of the line joining N and CI". This is intended to correspond to r as used by Venkatachalam et al.14.15 As the reference plane we use N I , CI", and the midpoint of the line joining Clpand C16. The sign of y is positive if C l r and Cl are on opposite sides of the reference plane. Previous Calculations of Conformational Energy of Proline Derivatives. Several studies have examined the effect of ring puckering on overall folding properties of proline-containing peptides and on statistical properties of polyproline and of polyhydroxyproline. These have utilized rather primitive treatments of ring puckering, since the main interest was e l s e ~ h e r e . Our ~ ~ -calculations ~~ provide important information about these relationships, as will be discussed below. Tonelli61,62reports calculations for isomerization involving the proline C"-C bond (#). Madison63a calculated energies for backbone conformations of cyclic (Pro-Gly)3. Madison and S ~ h e l l m a combined n ~ ~ ~ geometric calculations with C D calculations. Young et a1.64report torsions for minimum energy conformations of c-(L-Pro-L-Pro) based on the Lifson force field:65,66X I to x4 = 33,34, -23,2; @ = -16; J , = 26; w = -10. Corresponding values for c-(L-Pro-D-Pro) are -37, 36, -22, -1, -6, 5, -14. The ring conformational energy maps of Venkatachalam et al.14915 and earlier calculations of Ramachandran et al.,67 are discussed below. New Studies of Conformational Energies of Ac-Pro-OCH3. We have carried out extensive calculations of the energies of
Journal of the American Chemical Society
Table 11. Representative Conformational Energies and Torsions Calculated for Ac-Pro-OCH3 XI x2 x3 x4
X5
$
6 Vs
46.2 -44.7 23.0 6.2 -32.2 182.8' -89.9 1.74
28.7 -35.0 27.7 -10.3 -11.52 157.0 -16.3 O.OO
