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  • Title: Design and application of basic amino acids displaying enhanced hydrophobicity.
    Author: Kretsinger JK, Schneider JP.
    Journal: J Am Chem Soc; 2003 Jul 02; 125(26):7907-13. PubMed ID: 12823011.
    Abstract:
    Three noncoding basic amino acids, mono-, di-, and trimethyldiaminopropionic acid (mmdap, dmdap, and tmdap), have been synthesized for use in protein design. Covalent modification of a diaminopropionic acid (dap) side chain with an increasing number of methyl moieties results in a family of residues displaying short basic side chains with varying degrees of enhanced hydrophobic character. These residues may be used to introduce charged/polar interactions into the confining hydrophobic interior or interfacial spaces of proteins. As a demonstration of their utility, the ability of these residues to promote interior salt bridge formation at the helix/helix interface of GCN4-p1, a dimeric two-stranded coiled coil, was assessed. Heterodimerization mediated by buried salt bridge formation between a GCN4-based peptide containing either mmdap, dmdap, or tmdap at position 16 and an analogous peptide containing aspartic acid at the same position was studied. Mmdap-derived heterodimers are 0.5 kcal/mol more stable than the corresponding dap-derived heterodimers. This result indicates that the addition of one methyl group to the dap side chain can stabilize the heterodimeric fold. The stabilization can most likely be attributed to a decrease in the desolvation penalty incurred upon folding as well as enhanced van der Waals contacts in the folded state. The addition of three methyl groups to the dap side chain results in heterodimers that are significantly less stable than the corresponding dap-derived heterodimers, suggesting that increased steric bulk is not well accommodated in the interior of this protein. Unexpectedly, the addition of two methyl groups leads to homotrimerization of the dmdap-peptide. The resulting trimer is relatively stable (DeltaG(37)( degrees )(C) degrees = 11.8 kcal/mol) and undergoes cooperative thermal unfolding. The GCN4-p1 system exemplifies how small incremental changes in size and hydrophobicity can alter the folding preferences of a protein. Generally, this versatile suite of residues can be utilized in any protein and offer new options to the protein chemist.
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