Chem. 27 Section 1 Conformational Analysis TF: Walter E. Kowtoniuk wekowton@fas.harvard.edu Mallinckrodt 303 Liu Laboratory ffice hours are: Monday and Wednesday 3:00-4:00pm in Mallinckrodt 303 Course otes: 1.) Problem sets must be placed in your TF's mailbox (2nd floor Sci Center) BEFRE 11:00AM on the assigned date (usually Fridays) to receive credit. If this is a problem for any student he/she must contact me PRIR 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. 1
Ethane (anti, gauche, eclipsed): Saw horse gauche interaction +3.0 kcal/mol eclipsing interaction anti configuration eclipsing interaction gauche interaction ewman Projection Staggered conformation anti configuration 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. poor orbital overlap 60 o 120 o symmetry disallowed C- --> * C- Anti configuration maximizes hyperconjugation Butane C-C bonds anti +0.9 kcal/mol C-C bonds gauche C 3 120 o C 3 C 3 3 C Anti and gauche interactions of the methyl group dominate the confirmation of butane. otice that the methyl-methyl eclipsed interaction is too high energy to even be considered. 2
Penatane Syn-pentane +0.9 kcal/mol +0.9 kcal/mol anti-anti anti-gauche gauche-gauche +4-5 kcal/mol syn-pentane The key high energy interaction in the syn-pentane configuration to avoid is the 1,5 methylmethyl interaction. otice how the hydrogens on these methyls are brought into very close proximity. These disfavoring interactions only increase, as the substituents get larger. Cycohexane 1,3-diequitorial anti-anti ring flip 1,3-diaxial syn-pentane 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. +1.8 kcal/mol 3 C equitorial methyl 2-anti interactions C 3 axial methyl 2-gauche 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). vs. 3
The apparent syn-pentane interaction that is found in every cyclohexane is not actually a destabilizing interaction. The C- 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 +2.0 kcal/mol 3 1 3 1 Eclipsed conformation Staggered conformation Staggered conformation is disfavored due to electron repulsion between the system and the two C- 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). 3 C 3 C C 3 3 C C 3 +3.5 kcal/mol The effect of A1,3 strain is only amplified as the propene becomes substituted. otice the similarity between A1,3 and syn-pentane interactions. ote that the double methyl staggering would be even higher energy than the single methyl staggered. Amino Acid Conformation C 3 C 3 C 3 Valine 3 C 3 C C 3 C 3 3 C 3 C C 3 C 3 low energy conformation 3 C 3 C C 3 C 3 3 C 3 C C 3 C 3 +0.9 kcal/mole (additional gauche) 4
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 3 C C 3 rotate 1 and 2 C 3 C 3 low energy conformations rotate 2 rotate 2 C 3 C 3 3 C C 3 highly disfavored syn-pentane interactions 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 3 C rotate 1 C 3 C 3 rotate 2 3 C C 3 3 C 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 S 3 C rotate 1 3 C S rotate 3 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. S C 3 5
Peptide backbone R R R vs. A1,3 minimized 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. otice 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 -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. -elices are common motifs for accomplishing this, notice in the figure the -helix places the - and C= 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. owever, like -helices the key interaction is the - hydrogen bond Parallel 6
donor and the C= hydrogen bond acceptor of the peptide chain. Interestingly the adjacent peptide chains that come together to form the -sheet can be aligned parallel ( C directionality Anti-parallel the same) or antiparallel ( 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. ften 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. owever, 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. owever, 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
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. ydrophobic ydrophobic 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 8