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3D Structures of Biological Macromolecules Part
3 A Case Study in Structural Bioinformatics
C-H?-Interactions in Proteins
Jürgen Sühnel jsuehnel_at_fli-leibniz.de
Leibniz Institute for Age Research, Fritz Lipmann
Institute, Jena Centre for Bioinformatics Jena /
Germany
Supplementary Material www.fli-leibniz.de/www_bio
c/3D/
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C-H...?-Interactions in Proteins
?-system
C H
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C-H...?-Interactions Well-known in small
molecules
Kooijman et al, Acta Cryst. C. 2000, 56, 481-483
Benzene and analogous compounds dissolve
exothermically in chlorofom. M. Tamres. Aromatic
compounds as donor molecules in hydrogen
bonding. J. Am. Chem. Soc. 1952, 74, 3375-3378.
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C-H...?-Interactions in Proteins
Except for a few reports on the occurrence
of C-H...?-interactions in selected
structures there has been no systematic study for
proteins.
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C-H...?-Interactions in Proteins Database
Crystal structures with a resolution of 3.0 Å or
better R-factor 25 or lower Minimal chain
length 40 Maximum amino acid identity
25 PISCES web server
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C-H...?-Interactions in Proteins
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C-H...?-Interactions in Proteins
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C-H...?-Interactions in Proteins
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C-H...?-Interactions in Proteins Geometrical
Selection
Distance C-X lt 4.5 Å Distance Hp-X lt 1.2 Å (aro),
1.0 Å (non-aro) Angle C-H-X gt 120 º
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C-H...?-Interactions in Proteins Aims
Analysis of C-H...?-interactions occurring in
proteins

• Geometry
• Which donor atom types and which ?-systems are
  involved ?
• Where in proteins do C-H... ?-interactions
  occur ?
• Are there any secondary structure and
  neighbourhood relations ?

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C-H...?-Interactions in Proteins
dCX fraction lt 4.0 Å 69 lt 4.1 Å 78 lt
4.2 Å 86 lt 4.3 Å 92 lt 4.4 Å 96
dCX 3.74 3.93 Å
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C-H...?-Interactions in Proteins
Donor / acceptor Aro-? Am-? Ac-? Arg-?
Total C?-H 1,832 437 568 712 3,549
(1,01) (0,34) (0,31) (0,99) Cali-H 14,487 2,63
8 3,861 2,584 23,570 (1,95) (0,51) (0,52) (0,88
) Caro-H 2,687 361 608 312
3,968 (3,43) (0,66) (0,77)
(1,0) Total 19,006 3,436 5,037 3,608 31,087
Acceptors Aro - aromatic ring His, Phe, Trp,
Tyr Am - amide group Asn, Gln Ac -
carboxylate group Asp, Glu Arg - amidinium
group Arg
Donors C?-H - total number of aa plus number
of Gly Cali-H - all alipahtic C-H groups except
for C?-H Caro-H - all aromatic C-H groups
Non-redundant database of 1154 protein chains
with 285,794 amino acids
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C-H...?-Interactions in Proteins
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C-H...?-Interactions in Proteins
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The 15 interactions identified occur in all parts
of the protein. Some of them are completely
buried and others are partially exposed to the
solvent.
?B-eye-lens-crystallin (1amm, 1.2 Å)
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Interactions are referred to as local if the
sequence distance is smaller than 10. 41 of
C-H...?-interactions are local.?
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C-H...?-Interactions in Proteins

• 63 of this interaction type are local.
• 89 of the 3 peak interactions occur in
  helices.
• This interaction may be a major stabilizing
  element
• in ?-helices.

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cytochrome P450 (1bu7)
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L-aminopeptidase D-Ala-esterase/amidase (1b65)
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C-H...?-Interactions in Proteins
M. Brandl, M. S. Weiss, A. Jabs, J. Sühnel, R.
Hilgenfeld. C-H...? interactions in proteins. J.
Mol. Biol. 2001, 307, 357-377
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C-H...?-Interactions in Proteins
C-H...? and C-H...O/N interactions are
opportunistic ???
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C-H...?-Interactions in Proteins

• Most prominent are interactions between
• aliphatic or aromatic C-H donors and aromatic
  acceptors.
• About three quarters of all Trp-rings, half
  of all Phe- and Tyr-rings
• and a quarter of His-rings are involved as
  acceptors in
• C-H...?-interactions.
• On the donor side there is a preference for
  aromatic C-H groups,
• for prolines and for the long extended aliphatic
  amino acids
• Lys, Arg and Met.
• C-H...?-interactions involving aromatic groups
• either as donor or as acceptor are found mostly
  in the interior
• of the protein. The more hydrophilic the
  participating groups are,
• the closer to the surface are the interactions
  located.
• It is likely that C-H...?-interactions
  contribute significantly to
• overall protein stability.

M. Brandl, M. S. Weiss, A. Jabs, J. Sühnel, R.
Hilgenfeld. C-H...? interactions in proteins. J.
Mol. Biol. 2001, 307, 357-377.
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More Hydrogen Bonds for the (Structural)
Biologist
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More Hydrogen Bonds for the (Structural)
Biologist
A general concept of hydrogen bonding in
proteins is emerging. This concept involves not
only N-H and O-H donor groups, but also C-H, and
not only N and O as acceptor groups, but also
?-systems. We postulate that the incorporation
of the entirety of these interactions leads to a
more complete description of protein structures.
M. S. Weiss, M. Brandl, J. Sühnel, D. Pal, R.
Hilgenfeld. More hydrogen bonds for the
(structural) biologist. Trends Biochem. Sci.
2001, 26, 521-523.
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More Hydrogen Bonds for the (Structural)
Biologist
M. S. Weiss, M. Brandl, J. Sühnel, D. Pal, R.
Hilgenfeld. More hydrogen bonds for the
(structural) biologist. Trends Biochem. Sci.
2001, 26, 521-523.
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More Hydrogen Bonds for the (Structural)
Biologist
phospholipase C (PDB code 1ah7)
Classical N-H...O (helix192-204)
C?-H...O (LYS153-Val149)
C?1-H...? (Trp238-Phe94)
N-H...? (Ser63-Tyr61)
M. S. Weiss, M. Brandl, J. Sühnel, D. Pal, R.
Hilgenfeld. More hydrogen bonds for the
(structural) biologist. Trends Biochem. Sci.
2001, 26, 521-523.
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More Hydrogen Bonds for the (Structural)
Biologist

• Incorporation of the results obtained in
• structure prediction and refinement programs
• Global Phasing Ltd. (U.K.) ???
• Identification of examples for the structural
  and functional relevance of
• the new interaction types

M. S. Weiss, M. Brandl, J. Sühnel, D. Pal, R.
Hilgenfeld. More hydrogen bonds for the
(structural) biologist. Trends Biochem. Sci.
2001, 26, 521-523.