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Calculation of ν-electronic charge densities and bond orders in 4-bromoestrone and 4-bromoestradiol
PRELIMINARY NOIES
601
Pl~ 4 lo26
Calculation of ~-electronic charge densities and bond orders in 4-bromoestrone and 4-bromoestradiol The interaction of steroid hormones and their metabolites with proteins has been a subject of considerable interest in recent years. The first phase in such an interaction is a binding of the substrate to the protein molecule. Steroids are known to form diverse types of associations with proteins, e.g. by weak dissociable attachments with strengths of the order of hydrogen bonds z, amide linked complexes 2 or even highly stable covalently bonded complexes 3-6. A study of the electronic structure of the steroids is expected to elucidate the manner of possible attachment of the molecules in question. With this idea in mind the ~-electronic structure of two steroids, viz. : 4-bromoestrone and 4-bromoestradiol have been worked out and are presented in this note. The detailed atomic structure of these two molecules have been determined recentlyT,s and the calculations are based on them. The method used for the calculation is the PARISER--PARRL C A O - S C F (Linear Combination of Atomic Orbitals-Self Consistent Field) method 9 and the parameter choice is on the same lines as in the calculation by GRABE1° on some nueleotides. One improvement has been the use of experimental interatomic distances based on X-ray diffraction data. In 4-bromoestrone there are two regions which carry ~-electrons: ring A and the carbonyl group at position 17. In 4-bromoestradiol only ring A carries mobile ~-electrons, the lone pair electrons on the oxygen at C-I 7 being localised. In the case of ring A we have taken 8 ~-electrons--6 from the three double bonds and the lone pair electrons on the oxygen at C-3. The carbonyl group in the case of 4-bromoestrone carries 2 ~-electrons. The inductive effect of bromine substituted on C-4 has been taken account of by considering C-4 as a heteroatom. The perturbation term in the Hamiltonian due to this has been obtained from a recent paper by GODFREY AND MURRELL 11. CH3
01.2o
Br
O
CM3
OH
Be
CH 3
Br
CN 3
01-4
Br
Fig. I. Some bond lengths and bond angles in 4-bromoestrone and 4-bromoestradiol (from refs. 7 and 8).
Biochim. Biophys. Acta, 94 (1965) 6oi-6o3
602
PRELIMINARY NOTES
The bond lengths and angles in 4-bromoestrone and 4-bromoestradiol as obtained by NORTON, KARTI-IAAND LU%s are given in Fig. i. The x-electronic charge densities and bond orders (according to COULSO~'S12 definition) are presented in Fig. 2. The SCF molecular orbitals and their energies are given in Table I. CN 3
0
CH 3
0 +0.366
~g q~ 0 ~1 "gO
+0.055 -0.224
0.458
I Bv
,o.85o
CH 3
I Br
OH
CH 3
OH
0.134 0.453
NO y ~ e - ' ~ ~°u ~
HO"
[
+ 0.786
"r;o.158
1
v
Br
Br
Fig. 2. ~-electronic charge densities a n d bond orders in 4-bromoestrone and 4-bromoestradiol. TABLE I SELF
CONSISTENT
FIELD
MOLECULAR
ORBITALS
AND
THEIR
ENERGIES
IN
4-BROMOESTRONE
AND
4-BROMOESTRADIOL
Orbital energy (eV)
4-Bromoestrone (ring A)
--14.215 --IO.872 -- 9.688 -- 6.346 + 1.O73 + 1.889 + 4-398
4-Bromoestradiol (ring A)
--13.747 --II.O26 -- 9.415 -- 5.800 + 1.564 + 2.825 + 5.103
4-Bromoestrone (carbonyl group)
- - 15.390 o.o21
Orbital coefficients C-I
C-2
C-3
o.515 --O.O36 o.452 -0.370 --o.352 0.295 --o.421
O.679 --o.356 --o.186 O.141 --o.172 --O.41o o.4ol
0.245 0.502 --0.472 0.029 o-155 0.524 0.4o6
0.356 0.086 --0.423 --0.504 0.349 --0.423 --0.364
o.718 0.347 0.258 o.19o 0.275 --o.417 0.o36 o.381 o.586 --0.277 --0.055 0.453 0.624 --0.020 --0.030 0.031 --0.308 --0.047 0.440 0.673 --0.443 --O.O23 0-345 --O.447 o.581 --O.lO2 0.599 --0.337 ---0.242 0-074 o.316 --0.469 o.405 --O.4O9 --0.223
C-z 7
O-z 7
O.28O o.365 o.511 0.o09 0.589 0.079 o.417
0.563 0.826 0.826 --0.563
Biochim. Biopl,ys. Acta, 94 (I965) 6Ol-6o3
C-4
C-5
C-Io
0- 3
O.280 O.165 O.154 O.25O o.137 O.522 O . 6 2 1 --O.247 --0.545 --0.426 0.042 --o.141 --o.481 --0.004 0.424 0.657 0.507 --0.356 --o.158 0.302 --O.lO5 o.512 --0.478 0.487 --0.326 0.360 --0.394 --o.311
PRELIMINARY NOTES
603
These values are likely to be directly useful for the study of covalent binding although extrapolation to biologically active estrogens which are not brominated is not possible presently and must await comparable X-ray data on natural estrogens and reliable :information on the biological activity of brominated derivatives. However, one would recall that HECKER AND MUELLER5 have stated that the substitution of fluorine at C-4 of steroids does not affect the rate of covalent binding to protein. One direction in which we are continuing theoretical research in our Department is to locate the possible site of amide linkage and to see how such a link would modify the electronic structure along lines parallel to the investigations of PULLMAN AND PULLMAN 13 o n the carcinogenic hydrocarbons. One of the authors (K.S.) thanks the Indian Council of Medical Research for a fellowship grant for doing this work.
Department of Biophysics, All India Institute of Medical Sciences, New Delhi (India) I 2 3 4 5 6 7 8 9 io II 12 13
K . SUNDARAM-
R. K. MISHRA
U. WESTPttAL, Mechanism of Action of Steroid Hormones, P e r g a m o n Press, L o n d o n , 1961, p. 33~ B. F. ERL2kNGER, V. BOREK, S. M. BEISER AND S. LIEBERMAN, f . Biol. Chem., 228 (1957) 713 I. L. RIEGEL AND G. C. MUELLER, J. Biol. Chem., 21o (1954) 249. W. ZILLIG AND G. C. MUELLER, Federation Proc., 15 (1956) 503 . E. HECKER AND G. C. MUELLER, J. Biol. Chem., 233 (1958) 991. C. HEIDELBERGER AND M. G. MOLDt~NHAUER, Cancer Res., 16 (1956) 442. D. A. NORTON, G. N. KARTHA AND C. T. LU, Acta Cryst., 16 (1963) 89. D. A. NORTON, G. N. KARTHA AND C. T. LU, Acta Cryst., 17 (1964) 77. R. PARISER AND I~. G. PARR, J. Chem. Phys., 21 (1953) 466. B. GRABE, Arkiv Fysik, 17 (196o) 97M. GODFRF.Y AND J. N. MURRI~LL, Proc. Roy. Soc. London., Set. A, 278 (I964) 64. C. A. COOLSON, Valence, Oxford U n i v e r s i t y Press, London, 1961, p. 259. A. PULLM~,N AND B. PULLMAN, Advan. Cancer Res., 3 (1955) 117.
Received November I9th, 1964 Biochim. Biophys. Acta, 94 (1965) 6Ol-6O3.
PN 41027
Helix formation by isoguanosine Dilute aqueous solutions of isoguanosine [(erotonoside; 2-keto-6-amino-9-fl-Dribofuranosylpurine; structure shown in Fig. I) the nucleoside was first isolated from croton beans; by CHERBALIEZAND BERNHARD1. It was synthesized by DAVOLL 2, whose preparative procedure we have followed, omitting the lead salt step but using large amounts of charcoal for purification. Our material had the same ultraviolet spectra in acid, basic, and neutral solution as those reported by DAVOLLand the same RF value in the solvent system he reported. The compound was homogeneous when examined b y paper chromatography in four other solvent systems. Further confirmation of structure was provided by deamination to xanthosine, identified by ultraviolet and infrared spectroscopy. DAVOLL noted during the deamination of 2,6-diaminopurine riboside the formation of a "gelatinous mass" but did not further characterize t h e Biochim. Biophys. Acta, 94 (1965) 603-606-
601
Pl~ 4 lo26
Calculation of ~-electronic charge densities and bond orders in 4-bromoestrone and 4-bromoestradiol The interaction of steroid hormones and their metabolites with proteins has been a subject of considerable interest in recent years. The first phase in such an interaction is a binding of the substrate to the protein molecule. Steroids are known to form diverse types of associations with proteins, e.g. by weak dissociable attachments with strengths of the order of hydrogen bonds z, amide linked complexes 2 or even highly stable covalently bonded complexes 3-6. A study of the electronic structure of the steroids is expected to elucidate the manner of possible attachment of the molecules in question. With this idea in mind the ~-electronic structure of two steroids, viz. : 4-bromoestrone and 4-bromoestradiol have been worked out and are presented in this note. The detailed atomic structure of these two molecules have been determined recentlyT,s and the calculations are based on them. The method used for the calculation is the PARISER--PARRL C A O - S C F (Linear Combination of Atomic Orbitals-Self Consistent Field) method 9 and the parameter choice is on the same lines as in the calculation by GRABE1° on some nueleotides. One improvement has been the use of experimental interatomic distances based on X-ray diffraction data. In 4-bromoestrone there are two regions which carry ~-electrons: ring A and the carbonyl group at position 17. In 4-bromoestradiol only ring A carries mobile ~-electrons, the lone pair electrons on the oxygen at C-I 7 being localised. In the case of ring A we have taken 8 ~-electrons--6 from the three double bonds and the lone pair electrons on the oxygen at C-3. The carbonyl group in the case of 4-bromoestrone carries 2 ~-electrons. The inductive effect of bromine substituted on C-4 has been taken account of by considering C-4 as a heteroatom. The perturbation term in the Hamiltonian due to this has been obtained from a recent paper by GODFREY AND MURRELL 11. CH3
01.2o
Br
O
CM3
OH
Be
CH 3
Br
CN 3
01-4
Br
Fig. I. Some bond lengths and bond angles in 4-bromoestrone and 4-bromoestradiol (from refs. 7 and 8).
Biochim. Biophys. Acta, 94 (1965) 6oi-6o3
602
PRELIMINARY NOTES
The bond lengths and angles in 4-bromoestrone and 4-bromoestradiol as obtained by NORTON, KARTI-IAAND LU%s are given in Fig. i. The x-electronic charge densities and bond orders (according to COULSO~'S12 definition) are presented in Fig. 2. The SCF molecular orbitals and their energies are given in Table I. CN 3
0
CH 3
0 +0.366
~g q~ 0 ~1 "gO
+0.055 -0.224
0.458
I Bv
,o.85o
CH 3
I Br
OH
CH 3
OH
0.134 0.453
NO y ~ e - ' ~ ~°u ~
HO"
[
+ 0.786
"r;o.158
1
v
Br
Br
Fig. 2. ~-electronic charge densities a n d bond orders in 4-bromoestrone and 4-bromoestradiol. TABLE I SELF
CONSISTENT
FIELD
MOLECULAR
ORBITALS
AND
THEIR
ENERGIES
IN
4-BROMOESTRONE
AND
4-BROMOESTRADIOL
Orbital energy (eV)
4-Bromoestrone (ring A)
--14.215 --IO.872 -- 9.688 -- 6.346 + 1.O73 + 1.889 + 4-398
4-Bromoestradiol (ring A)
--13.747 --II.O26 -- 9.415 -- 5.800 + 1.564 + 2.825 + 5.103
4-Bromoestrone (carbonyl group)
- - 15.390 o.o21
Orbital coefficients C-I
C-2
C-3
o.515 --O.O36 o.452 -0.370 --o.352 0.295 --o.421
O.679 --o.356 --o.186 O.141 --o.172 --O.41o o.4ol
0.245 0.502 --0.472 0.029 o-155 0.524 0.4o6
0.356 0.086 --0.423 --0.504 0.349 --0.423 --0.364
o.718 0.347 0.258 o.19o 0.275 --o.417 0.o36 o.381 o.586 --0.277 --0.055 0.453 0.624 --0.020 --0.030 0.031 --0.308 --0.047 0.440 0.673 --0.443 --O.O23 0-345 --O.447 o.581 --O.lO2 0.599 --0.337 ---0.242 0-074 o.316 --0.469 o.405 --O.4O9 --0.223
C-z 7
O-z 7
O.28O o.365 o.511 0.o09 0.589 0.079 o.417
0.563 0.826 0.826 --0.563
Biochim. Biopl,ys. Acta, 94 (I965) 6Ol-6o3
C-4
C-5
C-Io
0- 3
O.280 O.165 O.154 O.25O o.137 O.522 O . 6 2 1 --O.247 --0.545 --0.426 0.042 --o.141 --o.481 --0.004 0.424 0.657 0.507 --0.356 --o.158 0.302 --O.lO5 o.512 --0.478 0.487 --0.326 0.360 --0.394 --o.311
PRELIMINARY NOTES
603
These values are likely to be directly useful for the study of covalent binding although extrapolation to biologically active estrogens which are not brominated is not possible presently and must await comparable X-ray data on natural estrogens and reliable :information on the biological activity of brominated derivatives. However, one would recall that HECKER AND MUELLER5 have stated that the substitution of fluorine at C-4 of steroids does not affect the rate of covalent binding to protein. One direction in which we are continuing theoretical research in our Department is to locate the possible site of amide linkage and to see how such a link would modify the electronic structure along lines parallel to the investigations of PULLMAN AND PULLMAN 13 o n the carcinogenic hydrocarbons. One of the authors (K.S.) thanks the Indian Council of Medical Research for a fellowship grant for doing this work.
Department of Biophysics, All India Institute of Medical Sciences, New Delhi (India) I 2 3 4 5 6 7 8 9 io II 12 13
K . SUNDARAM-
R. K. MISHRA
U. WESTPttAL, Mechanism of Action of Steroid Hormones, P e r g a m o n Press, L o n d o n , 1961, p. 33~ B. F. ERL2kNGER, V. BOREK, S. M. BEISER AND S. LIEBERMAN, f . Biol. Chem., 228 (1957) 713 I. L. RIEGEL AND G. C. MUELLER, J. Biol. Chem., 21o (1954) 249. W. ZILLIG AND G. C. MUELLER, Federation Proc., 15 (1956) 503 . E. HECKER AND G. C. MUELLER, J. Biol. Chem., 233 (1958) 991. C. HEIDELBERGER AND M. G. MOLDt~NHAUER, Cancer Res., 16 (1956) 442. D. A. NORTON, G. N. KARTHA AND C. T. LU, Acta Cryst., 16 (1963) 89. D. A. NORTON, G. N. KARTHA AND C. T. LU, Acta Cryst., 17 (1964) 77. R. PARISER AND I~. G. PARR, J. Chem. Phys., 21 (1953) 466. B. GRABE, Arkiv Fysik, 17 (196o) 97M. GODFRF.Y AND J. N. MURRI~LL, Proc. Roy. Soc. London., Set. A, 278 (I964) 64. C. A. COOLSON, Valence, Oxford U n i v e r s i t y Press, London, 1961, p. 259. A. PULLM~,N AND B. PULLMAN, Advan. Cancer Res., 3 (1955) 117.
Received November I9th, 1964 Biochim. Biophys. Acta, 94 (1965) 6Ol-6O3.
PN 41027
Helix formation by isoguanosine Dilute aqueous solutions of isoguanosine [(erotonoside; 2-keto-6-amino-9-fl-Dribofuranosylpurine; structure shown in Fig. I) the nucleoside was first isolated from croton beans; by CHERBALIEZAND BERNHARD1. It was synthesized by DAVOLL 2, whose preparative procedure we have followed, omitting the lead salt step but using large amounts of charcoal for purification. Our material had the same ultraviolet spectra in acid, basic, and neutral solution as those reported by DAVOLLand the same RF value in the solvent system he reported. The compound was homogeneous when examined b y paper chromatography in four other solvent systems. Further confirmation of structure was provided by deamination to xanthosine, identified by ultraviolet and infrared spectroscopy. DAVOLL noted during the deamination of 2,6-diaminopurine riboside the formation of a "gelatinous mass" but did not further characterize t h e Biochim. Biophys. Acta, 94 (1965) 603-606-