Peptide bond thermodynamic parameters

The parameters that control epimerization in a peptide-bond-forming reaction can be assessed in terms of their thermodynamic and kinetic components. Thermodynamic effects are those that stabilize the deprotonated activated intermediate or the protonated tertiary amine. Kinetic effects are expressed based on the degree of steric hindrance between the tertiary amine and activated intermediate. Table 4 summarizes these contributions and shows examples of high, moderate, and low propensities for contribution to the intrinsic rate of racemization among the various parameters. 

Based on early reports that 2,2-dimethylthiazolidine carboxylic acid gives rise exclusively to the ds-amide bond isomer in a model peptide [77], the (2S)-5,5-dimethylproline (Dmp, 21) was synthesized and analyzed for its propensity to stabilize the cis-isomeric state [78,79]. For Boc-Phe-Dmp-OMe and Ac-Tyr-Dmp-Asn-OH only a cis conformer was detected, while for Ac-Asn-Dmp-Tyr-OH the high content of ds-amide bond was found to slightly decrease in function of temperature from 90.3% at 6°C to 78.9% at 80 °C. This allowed the extraction of the thermodynamic parameters for the CTI (Table 11.5). In contrast to (2S)-5,5-dimethyl-proline, the (2S)-3,3-dimethylproline leads only to a slight increase of the cis isomer population of the related N-acetyl N-methylamide derivative compared with proline. However, the rates of cis-to-trans and trans-to-cis isomerization were strongly reduced, a fact that was attributed to steric interactions between the 3-methyl groups and the C-terminal amide that restrict the values away from rp 0° [80]. 

As indicated in Chapter III, step 1 of the fibrinogen-fibrin conversion is an example of a limited proteolytic reaction in which hydrolysis does not go to completion. Side-chain hydrogen bonding may stabilize the peptide bond in the manner indicated in Chapter III. We shall therefore discuss the reversibility of step 1 and the thermodynamic parameters for the equilibrium (Laskowski et al., 1960b). As in the case of the kinetic experiments discussed in Section 5b, the medium used was 1 molar NaBr at pH 5.3 to prevent polymerization of fibrin monomer, and the analysis for f was carried out using TAMe as a thrombin inhibitor, as already mentioned The equilibrium position was approached from both directions. 

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