Free Energy of Transfer for Protein Burial

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Free Energy of Transfer for Protein
Burial Crystal structures of 37 proteins were
examined amino acid surface ? amino acid
buried f (Nb/?Nb)/(Ns/?Ns) where Nb
frequency of amino acid burial in the protein
interior Ns frequency of occupancy on the
protein surface by the same amino acid ?Nb?Ns
sum of amino acids buried on surface ?burialG
-RTln f Criterion used for surface/burial
accessable surface area ASA ASA surface
area of aminoacid in the protein area of
aminoacid in the extended tripeptide
glyNHRCHCOgly where R amino acid side chain in
question Miller, S. Janin,J. Lesk, A. M.
Chothia. J. Mol. Biol 1987. 196, 641.
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Side Chain Hydrophobicity Solubility of
R-CHCONH2 in water ? octanol
NHCOCH where R
amino acid side chain K solubility in
1-octanol solubility in
water ?w?oG -RTln K Fauchere, L. Pliska, V.
Eur J.Med. Chem.-Chim. Ther. 1983, 18, 369.
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Free Energy of Tranfer For Residue Burial
(DburialG) and Hydrophobicity (Dw?oG) at 300
K. R Dw?oG DburialG kJ
mol-1 alanine -CH3 -1.8 -0.8 asparagine -CH2C
ONH2 3.4 2.9 aspartic acid -CH2CO2H 4.4
3 cysteine -CH2SH -5.6 -2.8 glutamine -CH2CH
2CONH2 1.3 3.1 glutamic acid -CH2CH2CO2H
3.6 4.6 histidine -CH2(C3H3N2) -0.8 -0.2 is
oleucine -C(CH3)CH2CH3 -10.3 -3.1 leucine -CH2
CH(CH3)2 -9.7 -2.7 lysine -(CH2)4NH2 5.6
8.4 methionine -CH2CH2SCH3 -7 -3 phenylalanine
-CH2C6H5 -10.2 -2.8 serine -CH2OH 0.2
1.4 threonine -CH(CH3)OH -1.5
1.1 tryptophane -CH2(C8H6N) -12.8 -1.9 tyrosin
e -CH2(C6H4OH) -5.5 0.9 valine -CH(CH3)2 -6
.9 -2.6
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Why is there scatter in the plot of ?w?oG vs
?burialG ?
Consider an aminoacid in the exterior of a
protein and compare it to an aminoacid in the
interior. Then consider the same aminoacid in
water and in octanol.
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Is there anyway to correct for loss of side chain
mobility on the interior of the protein?
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Contributions to Entropy Accompanying
Melting Sfus Strans Srot Svib Selec
Srot Srigid body rot Sconf During melting,
lets assume that Svib Selec are not
significantly affected. For an ideal gas at 298
K Strans 37.0 3/2Rln(M/40) Srigid body
rot 11.5 R/2ln(Im3/?e) Rln(n) where M
molecular weight Im3 product of the three
moments of inertia about the center of gravity of
the molecule ?e external symmetry number n
number of optical isomers. Since translation and
rigid body molecular rotation vary as the
logarithm of molecular weight and moment of
inertia, respectively, their contribution to the
total entropy change would be similar for a
related group of compounds.
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If the contribution of an amino acid side chain
(R) to the entropy of fusion is compared to that
of a standard (CH3), then Sfus(R) Sfus(CH3)
?Strans ?Srigid body rot ?Sconf and if
Strans(R) ? Strans(CH3) Srigid body rot(R) ?
Srigid body rot(CH3) then Sfus(R)
Sfus(CH3) ? ?Sconf or ? Sconf(R) where
Sconf(R) is the entropy change as a result of the
gain or loss of conformational flexibility
relative to methyl.
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R DtpceS TDDS Dw?oG
Dw?oG DburialG
-TDDS alanine -CH3 17.6 0
-1.8 -1.8 -0.8 asparagine
-CH2CONH2 35 5.1
3.4 8.7 2.9 aspartic acid -CH2CO2H
37.3 5.8 4.4 10.2
3 cysteine -CH2SH 30.1 3.7
-5.6 -1.9 -2.8 glutamine-CH2CH2CO
NH2 42.1 7.2 1.3 8.5
3.1 glutamic acid -CH2CH2CO2H 44.3 7.9
3.6 11.5 4.6 histidine -CH2(C3H3N2)
32.2 6.0 -0.8 5.2
-0.2 isoleucine -CH(CH3)CH2CH3 25.9 2.4
-10.3 -7.9 -3.1 leucine -CH2CH(CH3)2
25.9 2.4 -9.7 -7.3
-2.7 lysine -(CH2)4NH2 76.2 17.3
5.6 22.9 8.4 methionine -CH2CH2SCH3
33.9 4.4 -7 -2.6
-3 phenylalanine -CH2C6H5 34.5 5.0
-10.2 -5.2 -2.8 serine -CH2OH
23.6 1.8 0.2 2
1.4 threonine -CH(CH3)OH 24.2 2.0
-1.5 0.5 1.1 tryptophane
-CH2(C8H6N) 43.5 7.6 -12.8 -5.2
-1.9 tyrosine -CH2(C6H4OH) 39.9 6.6
-5.5 1.1 0.9 valine -CH(CH3)2
18.8 0.4 -6.9 -6.5 -2.6
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Protein side chain conformational entropy
derived from fusion data - comparison with other
empirical scales Sternberg, M. J. E. Chickos,
J. S. Protein Engineering 1994, 7, 149 - 155.