Peptide trans form

Figure 6.9 (a) Peptide units can adopt two different conformations, trans and cis. In the trans-form the C=0 and the N-H groups point in opposite directions whereas in the c/s-form they point in the same direction. For most peptides the trans-form is about 1000 times more stable than the c/s-form. (b) When the second residue in a peptide is proline the trans-form is only about four times more stable than the c/s-form. C/s-proline peptides are found in many proteins. 

The recognition that short chain / -peptides can form regular secondary structures initially came from detailed conformational analysis of y9 -peptides 1 and 66 (which incorporates a central (2S,3S)-3-amino-2-methylbutanoic acid residue) by NMR in pyridine-d5 and CD3OH [10, 103, 164] and homooUgomers (as short as four residues) of trons-2-amino-cyclohexanecarboxyhc acid (trans-ACHC) (e.g. hex-amer 2 for the (S,S) series) by NMR and X-ray diffraction [6, 126, 159]. 

Most peptide bonds in proteins take on the trans conformation (see p. 66). Only bonds with proline residues (-X-Pro-) can be present in both cis and trans forms. 

In cyclic peptides the cis- and frans-peptide bonds occur, with the cis form preferred in small cycles, and the trans form preferred in large systems (75AX(B)2035). The peptide bond is expected (68MI6) to deviate slightly from planarity in order to alleviate short-range interactions and bond-angle strain. 

Proline is an exceptional amino acid residue in that the cis-trans equilibrium only slightly favors the trans form in peptidyl-proline bonds. Small proline-containing peptides in solution contain some 5 to 30% of the cis (syn) isomer, as opposed to less than 0.1% of the cis isomers of the other amino acids.14 The cis form is even found in native proteins two of the four prolines in ribonuclease A... 

Co(trien)(NH3)2] + has been isolated, and only the meso trans isomers (197-198) with two different axial ligands, remain to be distinguished. There is also an extensive chemistry of N and C-alkylated derivatives of (178 180) as cA-[Co(OH)(trien)(OH2)] assists the hydrolysis of amino acid esters, amino acid amides, and peptides to form cis-fi (194) and cA-jS2-[Co(OA0(trien)] + (195)(( A = amino acid) complexes. Chiral alkylated trien ligands have the potential for chiral stereospecificity in such reactions. 

Figure 3.25. Trans and Cis Peptide Bonds. The trans form is strongly favored because of steric clashes that occur in the cis form.

Torsion angles, in addition, may be used to designate the conformation of the side chains. These are denoted by x (x X working along the chain away from Ca). The steric interactions within the side chains in the trans form of the peptide bond (u> = 180°) are much more favorable than those in the cis form (w = 0°), where there may also be steric interference with side chains from residues i- -2. If the residue i+1 is proline, however, the cis and trans forms (Figure 12.25) have similar energies. Proline is the only amino acid taking part in a cis peptide that is normally encountered in proteins. 

Tyr from water to an organic solvent, it is not very different from Phe, so we should not be surprised to find it in hydrophobic environments. Gly is an unusual amino acid, with only a hydrogen atom as side chain, and peptide bonds involving Gly residues can take up all sorts of conformations. Pro, which does not have a proton when in a peptide bond, clearly, is hydrophobic, cannot participate in hydrogen bonding, and has the unique capacity among the protein amino acids to be able to form cis-peptide bonds (there is a cis/trans prolyl isomerase to restore the trans form). 

Proton NMR studies of N-methyl formamide (NMF) and NMA at high dilution in deuterated solvents have shown that the level of cis isomer of NMF is 8% in water, 10.3% in chloroform, 8.8% in benzene, and 9.2% in cyclohexane, while the level of cis-NMA (a model for the secondary peptide bond) is 1.5% in water and does not change very much in nonpolar solvents [18]. Ab initio molecular calculations suggest that the small difference in dipole moments in cis and trans forms explain the relative insensitivity of amides to solvent change, unlike esters [22,41], This may be explained by nearly identical free energies of solvation for the two isomers [18]. The energy difference between cis and trans isomers in aqueous solution (AG° = 2.5 kcal mol-1) accounts for the preferential trans conformation adopted by most peptide bonds. Similar results were obtained with nonproline tertiary amides [22]. 

By use of site-directed mutagenesis in positions covering cis prolyl bonds, the proline has been replaced by nonproline amino acids. It came as a surprise that the secondary amide peptide bond formed in the substitution still adopts the thermodynamically disfavored cis conformation in many cases [25,26,132-135], Thus, to overcome the free energy costs of a cis secondary amide peptide bond of about 15 kj mol-1 the structural consequences favoring the trans conformation must be absent in the folded protein variant. Consequently, the CTI is largely retained in these protein variants [133],... 

In folded proteins the peptide bonds are usually in the trans conformation, which, for nonprolyl bonds,1 is much less strained than the energetically unfavorable cis conformation. For the peptide bonds that precede proline (prolyl bonds), however, the energy difference between the cis and trans states is small, and therefore cis prolyl bonds are found rather frequently in folded proteins. These cis prolyl bonds create a problem for protein folding. The incorrect trans forms predominate in the unfolded or nascent protein molecules, and the trans —> cis isomer-izations are intrinsically slow reactions because rotation about a partial double bond is required. Incorrect prolyl isomers in a protein chain strongly decelerate its folding. This is clearly seen for small single-domain proteins. Many of them refold within a few milliseconds when they contain correct prolyl isomers but when incorrect isomers are present, folding usually requires seconds to minutes. 

Fig. 1. Isomerization between the cis and trans forms of an Xaa-Pro peptide bond.

Cis/trans isomerism is not confined to prolyl bonds. Cis peptide bonds to residues other than proline (cis nonprolyl bonds) are, however, extremely rare in folded proteins because the trans form is strongly favored over cis. In short unstructured peptides 99.5—99.9% of nonprolyl peptide bonds are in the trans state (Scherer et al., 1998). Proteins that contain nonprolyl cis peptide bonds in their native states must therefore undergo trans —cis isomerizations of these bonds in virtually all refolding molecules. 

---