Peptides conformational effects

The effect of C ,C -disubstituted amino acids (aaAAs) on peptide secondary structure has been studied in recent years.2a d While longer side-chain C ,C -di-n-alkyl amino acids promote extended peptide conformation,23 alicyclic aaAAs, in which the Ca carbon forms a cyclic bridge with itself, such a 1-aminocyclopentane-l-carboxylic acid (Ac5c) and 1-aminocyclohexane-l-carboxylic acid (Ac6c), have helix-forming characteristics similar to those of 1 -aminoisobutyric acid (Aib).2ax... 

Schiller PW, Weltrowska G, Nguyen TM-D, Lemieux C, Chung NN, Marsden BJ, Wilkes BC. Conformational restriction of the phenylalanine residue in a cyclic opioid peptide analogue effects on receptor selectivity and stereospecificity. J Med Chem 1991 34 3125-3132. 

However, in a later study employing polymeric peptides of 5 to 50 residues assembled from block sequences, significant deviations of observed retention values from the predicted values were found for polypeptides larger than about 10 residues. These deviations for larger polypeptides were correctly interpreted as conformational effects. 

In the absence of secondary effects as part of the RPC distribution process(es), i.e., when no temperature- or ligand-mediated conformational effects, slow chemical equilibrium, or pH-dependent ionization events occur, then the resolution, Rsi, between two adjacent peptides separated under equilibrium or near-equilibrium conditions can be expressed as... 

Figure 4.6. Modulation of peptide conformational equilibrium can be achieved through systematic modifications of peptide sequences that direct receptor interactions toward therapeutic response, and away from untoward effects. A systematic peptide modification may lead to reduced concentrations of peptide conformations susceptible to metabolizing enzymes such as peptidases.

Since IFN- and IFN-a bind to the same receptor, the ability of the IFN- synthetic peptides to block both bovine and human IFN-a was examined. Interestingly, only three of the four inhibitory peptides were effective competitors of IFN-a. Cross-inhibition of IFN-a by the internal and carboxy-terminal peptides was observed and suggested that these residues may adopt a similar conformation in both molecules and bind to a common site on the receptor. The aminoterminal peptide failed to reduce IFN-a function entirely. Thus, either the IFN-a amino-terminus has a much higher affinity for receptor or the IFN- aminoterminus binds a unique site on the receptor complex that may be associated with its unique properties. As expected, none of the peptides blocked the antiviral activity of IFN- , which interacts with a different receptor. 

Replacement of carbon atoms in the cyclic aliphatic side chain of proline with nitrogen leads to the azaprolines where incorporation of an additional imino group may affect molecular recognition processes via electrostatic interactions. While the proline analogues imidazoli-dine-2-carboxylic acid (3-azaproline, 15) and pyrazolidine-3-carboxylic acid (5-azaproline, 16) allow for additional side-chain modifications in peptidomimetic structures, with pyr-azolidine-2-carboxylic acid (2-azaproline, 17) (Table 2), where the a-CH is replaced by nitrogen, the peptide backbone is modified with consequently strong conformational effects. 

Interestingly, one can use a Cys-Gly-Gly linker at the N- or C-terminal of the polypeptide chain in the design of disulfide-bridged coiled coils. The advantage of this approach is that the Cys-Gly-Gly linker allows complete flexibility of the polypeptide chains to adopt their most stable conformation, which includes different oligomerization states, while maintaining the polypeptide chains in a parallel manner. 49 In addition, the Cys-Gly-Gly linker eliminates the monomer-dimer equilibrium and the peptide concentration effect on stability, which is observed in two-stranded coiled-coil formation of noncovalent linked polypeptides. 49 861... 

Our next optimization step consisted in introduction of substituents in the 4-position of the aromatic peptide subunits of 3 [18]. These substituents should affect the rotation of neighboring amide groups by steric effects. More importantly, if they can form hydrogen bonds to the amide protons they should stabilize peptide conformations in which all NH groups point away from the cavity center. This effect would not only affect the flexibility but also the anion-binding ability of 3, because, for the latter, a conformation with converging NH groups is required. To... 

Systematic investigations revealed that anion binding is mainly prevented by the steric effects of the aromatic substituents. A cyclopeptide with methyl groups on the aromatic rings, for example, also binds no anions. The high cation affinity of 4a and 4b has to be attributed to the stabilizing effects of the aromatic substituents on peptide conformation, however, because the methyl-substituted peptide, in which the amide groups are not fixed in a certain orientation, has a cation affinity that is even lower than that of 3 [18]. 

Chou-Fasman parameters (Chou and Fasman, 1978) were identical for each of these peptides, as were the Zimm-Bragg s values (Scheraga, 1978) for helix formation. The peptides differ only in their hydrophobic periodicities (3.5 for peptides 1 and 2 2.0 for peptide 3) and chain lengths, thus allowing the effect of these parameters on peptide conformation to be investigated while keeping short-range interactions approximately constant. All three of these peptides adopted random conformations in very dilute, aqueous solutions, but peptides 2 and 3 could be induced to form... 

QUANTIFYING SOLVATION EFFECTS ON PEPTIDE CONFORMATIONS A QM/MM REPLICA EXCHANGE STUDY... 

Volk M, Kholodenko Y, Lu HSM, Gooding EA, DeGrado WF, Hochstrasser RM. Peptide conformational dynamics and vibrational Stark effects following photoinitiated disulfide cleavage. J Phys Chem B 1997 101 8607-8616. 

In general, a FRET quench readout is simple. A broad range of available fluorescence donors and acceptors allows cost-efficient operations in an industrialized HTS and automated compound profiling environment. On the other hand, the readout can suffer from inner filter effects due to high absorption coefficients of the dyes and fluorescence artifacts by the tested compounds, resulting in enhanced false positive and false negative rates. Moreover, the readout is limited to substrates in which short distances between donor and acceptor dye can be realized without disturbing the interaction of enzyme and substrate. The flexibility of the peptide conformation makes the prediction of the effective distance between the dyes and consequently the prediction of the FRET effect difficult. The distance between donor and acceptor cannot be easily approximated by the mean hydrodynamic radii of the dyes. 

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