Chem. 27 Section 1 – Conformational Analysis
Week of Feb. 6, 2006
W. E. Kowtoniuk
TF:
Walter E. Kowtoniuk
wekowton@fas.harvard.edu
Mallinckrodt 303 Liu Laboratory
Office hours are:
Monday and Wednesday
3:00-4:00pm in Mallinckrodt 303
Course Notes:
1.) Problem sets must be placed in your TF's
mailbox (2nd floor Sci Center) BEFORE
11:00AM on the assigned date (usually Fridays) to receive credit. If this is a problem for
any student he/she must contact me PRIOR to 11:00AM on the due date.
2.) Section attendance is mandatory. If there is ever a problem with making to a section
please email me in advance. I teach two sections we can easily work out any problems if
plans are made in advance.
3.) Please bring your blue book to section. We will commonly work through a number of the
problems in the blue book during section.
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Section 1 – Conformational Analysis
Week of Feb. 6, 2006
W. E. Kowtoniuk
Ethane (anti, gauche, eclipsed):
gauche interaction
H
H
Saw horse
anti configuration
gauche interaction
H
Newman Projection
H
H
H
H
H
H
H
eclipsing interaction
H
H
+3.0 kcal/mol
H
H
anti configuration
H
eclipsing interaction
HH
H
H
H
H
Staggered
conformation
H
H
H
Eclipsed
conformation
Anti configuration is preferred both due to sterics and electronics. Stericly placing the groups as
far away as possible is preferred (minimize eclipsing interactions). Electronically there is a
stabilizing hyperconjugation between anti substituents.
symmetry disallowed
poor orbital overlap
120o
60o
C-H --> * C-H
Anti configuration maximizes hyperconjugation
Butane
H
H
H
H
H3C
H
H
H
H
H
H
C-C bonds anti
H
H
H +0.9 kcal/mol
H
H
H
H
H
H
H
H
H
H
CH3
C-C bonds gauche
o
120
H
H
H
CH3
CH3
H
H
Anti and gauche interactions of the methyl group dominate the confirmation of butane. Notice
that the methyl-methyl eclipsed interaction is too high energy to even be considered.
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Section 1 – Conformational Analysis
Week of Feb. 6, 2006
W. E. Kowtoniuk
Penatane – Syn-pentane
H
H
H
H
H
H
H
H
H
H
H
H
H
H +0.9 kcal/mol H
H
H
H
H
H
H
H
+0.9 kcal/mol
H
H
H
H
H
H
H
H
+4-5 kcal/mol
H
H
H
H
H
H
H
gauche-gauche
H
anti-gauche
H
H
H
H
H
H
H
anti-anti
H
H
H
syn-pentane
The key high energy interaction in the syn-pentane configuration to avoid is the 1,5 methylmethyl interaction. Notice how the hydrogens on these methyls are brought into very close
proximity. These disfavoring interactions only increase, as the substituents get larger.
Cycohexane
H
H
H
H
H
H
H
H
H
ring flip
H
H
H
H
H
H
H
H
H
1,3-diaxial
syn-pentane
H
H
1,3-diequitorial
anti-anti
Along the lines of syn-pentane interaction is it easy to see that the diaxial chair enforces a synpentane interaction thus making it the high energy conformer.
H
+1.8 kcal/mol
H
H 3C
CH3
axial methyl
2-gauche interactions
equitorial methyl
2-anti interactions
Even without a methyl-methyl syn-pentane the axial conformer is disfavored. The axial
substituent has two gauche interactions with the ring thus for methyl an A value of 1.8kcal//mol
(0.9 kcal/mol x 2).
H
H
H
H
vs.
H
H
H
H
H
H
H
H
H
H
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Section 1 – Conformational Analysis
Week of Feb. 6, 2006
W. E. Kowtoniuk
The apparent syn-pentane interaction that is found in every cyclohexane is not actually a
destabilizing interaction. The C-H electrons that were previously repelling are bound to a
bridging methylene. This eliminates the disfavoring interactions while also placing the other
hydrogens in non-interacting positions.
Propene – A1,3 strain
H
H
H
H
H
3
H
+2.0 kcal/mol
H
1
H
H
H H
H
3
H
1
H
H
H H
H
H
Eclipsed
conformation
H
Staggered
conformation
H
H
H
H
H
H
Staggered conformation is disfavored due to electron repulsion between the system and the two
C-H bonds. In the eclipsed conformation the single hydrogen facing the system is
interacting with the nodal plane. This conformational preference is a result of A1,3 strain (or
allylic strain).
H 3C
H
H
H 3C
CH3
H 3C
H
CH3
H
+3.5 kcal/mol
CH3
CH3
CH3
The effect of A1,3 strain is only amplified as the propene becomes substituted. Notice the
similarity between A1,3 and syn-pentane interactions. Note that the double methyl staggering
would be even higher energy than the single methyl staggered.
Amino Acid Conformation
Valine
H
N
H 3C H
CH3
H
N
H
H
C
3
O
H
H
CH3
N
H 3C H
O
H
H
N
H3C H
CH3
H
O
CH3
N
H 3C H
O
H
low energy conformation
O
CH3
H
H
N
H3C H
H
H
CH3
H
N
H 3C H
H
CH3
O
O
H
N
H3C H
H
CH3
O
+0.9 kcal/mole (additional gauche)
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Section 1 – Conformational Analysis
Week of Feb. 6, 2006
W. E. Kowtoniuk
The low energy conformation of valine contains two gauche and two anti interactions. The
higher energy conformations of valine contain three gauche and one anti interaction. Thus the
energy difference between conformers is estimated at +0.9kcal/mol (>82% of the population).
Leucine
CH
H 3
N
H H
H
H
H 3C
H
CH3
rotate
1 and 2
O
N
H
H
H
rotate 2
H
H3C
O CH3
H
H
rotate 2
CH3
N
H H
low energy conformations
O
CH3
H
CH3
H
N
H
H
H
O
highly disfavored
syn-pentane interactions
H
The low energy conformation of leucine avoids syn-pentane interactions. Rotations of 1 and 2
lead to the creation of syn-pentane interactions. Two of these rotations are shown, although there
are more. The two low energy conformers are equal in energy and thus equally populated.
Isoleucine
H
N
H3C H
H
O
H
CH3
CH3
H
H
H
H3C
rotate 2
N
H
H
H
H
H
rotate 1
N
H
H3C
O
CH3
H
O
H
low energy conformation
Isoleucine is considered a rigid amino acid despite having seemingly free to rotate bonds.
Rotation of 1 generates two gauche interactions while rotation of 2 generates a syn-pentane
interaction. Therefore, isoleucine is 95% populated by this low energy conformer.
Methionine
H
H
N
H H
H
H
O
H3C
H
H
N
H
rotate 1
S
H 3C
H
H
S
N
H
rotate 3
O
H
S
H
H
H
CH3
H
O
H
Methionine is a floppy amino acid. The key to this added flexibility is the increased length of the
C-S bond relative to the C-C bond. There will be less efficient orbital overlap between C-S
relative to C-C, thus the bond length will increase. This greater length greatly diminishes the
conformational effects that lead to one conformer being favored over another. The
conformational analysis shows that there will be large distribution of conformers as there are few
distinct destabilizing interactions. The increased C-S length permits the syn-pentane and gauche
conformer to contribute to the total methionine population. Thus, it is not surprising to find that
many general enzymes – enzymes accepting multiple substrates – incorporate this flexible, yes
hydrophobic, amino acid into the active site of the enzyme.
5
Section 1 – Conformational Analysis
Week of Feb. 6, 2006
W. E. Kowtoniuk
Peptide backbone
O
H
A1,3 minimized
R
R
O
N
H
O
H
O
N
H
vs.
O
R
H
O
N
H
The key to conformation of the polypeptide chain is minimization of A 1,3 strain. The amide
nitrogen can delocalize into the carbonyl forming the resonance structures shown above. The key
to the polypeptide chain is noting that these resonance structures are representative off the amide
conformation and thus the conformation will be the one that minimized A 1,3. Notice that the
staggered conformation is not even considered; rather the primary factor is placing the small
hydrogen in plane with the system. Furthermore, due to the bulk of the amid side chains the
finding the cis configuration about the N-C double bond is rare. It can occur with proline and
glycine residues due to the smaller size (gly) and imposed rigidity (pro) of these amino acids.
Protein Folding
-helix
In all of the amide moieties of a peptide chain there is a hydrogen
bonded to the nitrogen (with the exception of proline). Additionally, on
each carbonyl oxygen there is a lone pair of electrons. The hydrogen
bound to the nitrogen represents a hydrogen bond donor while the
oxygen lone pair represents a hydrogen bond
acceptor. Proteins will fold in such a
way to maximize hydrogen bonding.
-Helices are common motifs for
accomplishing this, notice in the
figure the -helix places the N-H and
C=O moieties on the inside of the
helix forming hydrogen bonds while
also placing the side chains on the
exterior. The other figure shows the ribbon
structure representation of the -helix.
-sheet
Another motif for maximizing hydrogen
bonding between the peptide chain of amino
acid chains is the -sheet motif. In this case
the peptide chain of one amino acid chain
hydrogen bonds with the peptide chain of an
adjacent chain. However, like -helices the
key interaction is the N-H hydrogen bond
Parallel
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Section 1 – Conformational Analysis
Week of Feb. 6, 2006
W. E. Kowtoniuk
donor and the C=O hydrogen bond acceptor of the peptide
chain. Interestingly the adjacent peptide chains that come
together to form the -sheet can be aligned parallel (N C
directionality
Anti-parallel
the same) or
antiparallel
(N C
directionality
opposite). The
ribbon structures
highlight the -Turn
-turns are most significant because
they lead to a change in chain directionality.
The carbonyl oxygen hydrogen bond acceptor
and nitrogen hydrogen bond donor are separated by
10 atoms, as shown in the figure to the right.
Additionally, the figure points out the turns are
commonly generally containing a proline and glycine
residue. The proline provides the necessary structural
rigidity to force a turn
while the glycine is a
small and flexible
amino acid capable of
rotating to form the
necessary hydrogen
bond.
Salt Bridge
Salt bridges are electrostatic interactions between oppositely charged amino acid
residues. Often times these interactions involve positively charged arginine side chains and
negatively charged glutamate side chains. These interactions are most
important on the interior of proteins where there is a low dielectric
constant in the nonpolar core. However, salt bridges are found on the
surface of proteins with less overall energetic consequence due to the
higher dielectic constant of the surrounding environment
Disulfide Bonds
Disulfide bonds are formed when two thiols are oxidized to
release two electrons and two protons. These bonds are commonly
found between to cysteine side chains and are much stronger than
hydrogen bonds. However, since the inside of a cell is a reducing
environment disulfide bonds are generally not found on the inside of
a cell. They are frequently found in secreted proteins, such as
hormones like insulin. The dihedral angle of disulfide bonds are 90°
7
Section 1 – Conformational Analysis
Week of Feb. 6, 2006
W. E. Kowtoniuk
due to the hyperconjugation of the lone pair
on the S donating into theadjacent S-C
antibonding orbital. By placing the sulfur
lone pair antiperiplanar to the C-C bond the
orbital overlap is maximized thus providing a
strong conformational preference for 90° dihedral angles.
Hydrophobic
Hydrophobic amino acid side chains pack closely together when in aqueous media in
order to minimize their interaction with water. For
example phenylalanine, valine, and leucine pack into the
core of a protein, as shown, in order to minimize their
contact with the polar environment. By interacting with
each other the hydrophobic sidechains are effectively
solvating each other rather than being solvated by water.
Furthermore, when a hydrophobic structure is forced to
interact with water the water forms a highly organized
lattice called clathrate water. An example of these
clathrate structures is
shown below. Thus,
by folding hydrophobic side chains to the interior of the
protein this highly organized form of water is not present and
thus the folding of hydrophobic sidechains into the interior is
favored due to the greater entropy of not forming the clathrate
water.
Problems:
B06, B08, B11, C01, C04, C06, C09, C11, C12
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