Tolerance to amino acid variations

Tolerance to Amino Acid Variations in a HLA Class 11 Ligand... 

Tolerance to amino acid variations for binding of undecapeptides to HLA DR1 molecules was determined by calculating the sum of the absolute values of the ln(relC) for all 20 O/Xl0 sublibraries of one sequence position. For sequence positions that allow close contact of the amino acids to the DR1 molecule, low tolerance with respect to biological activity to amino acid variations was expected. In contrast, amino acids variations should be more tolerated in positions projecting away from the binding cleft. The X-ray structure... 

Figure 11.9. Tolerance to amino acid variations in the 11 sequence positions with respect to proliferation of the TCC 5G7. Data were calculated as described from the allele-specific DR2b- Activity Pattern and from the Recognition Pattern of TCC 5G7. Letters indicate amino acids from MBP (85-95).

Udaka K, Wiesmiiller K-H, Kienle S, Jung G, Walden P (1995) Tolerance to amino acid variations in peptides binding to the MHC class I protein H-2Kb, J Biol Chem 720 24130-24136. 

The utility of a sequence-activity model lies in its ability to predict the activity of variants that have not been measured, or to identify amino acid variations that contribute positively to a specific protein property and that can then be experimentally combined. To test our sequence activity model for heat-tolerant hydrolyzers of AAPL-p-NA, we analyzed the regression coefficients from the model, as shown in Figure 4. 

The principal component analysis also clusters related functional measures. We selected three representative activities based on the functional clustering shown in Figure 6 for further analysis activity towards AAPL-p-NA at pH 7.0, absolute activity towards AAPL-p-NA following 5 minutes at 65°C and activity towards casein. For each of these activities we constructed PLSR models similar to that shown in Figure 3, and calculated the regression coefficients for each amino acid variation as shown for thermal tolerance in Figure 4. The changes calculated to contribute positively to each property are shown in Table 1. 

The amino terminal position (residues before the first cysteine) of a-conotoxins may be occupied by a wide range of amino acids (Gly, Glu, He, Tyr and the dipeptide -Gly-Lys-). In fact, (des-Glu )a-conotoxin GI was found to have practically the same activity as the natural peptide (Gray et al., 1985). It is believed that the positive amino group at the terminus is important for binding to the receptor and a variation of side chains can be tolerated. 

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