Conformationally Constrained Amino Acids in Peptide Design
7 Pages Posted: 9 Jul 2017
Date Written: April 19, 2016
Synthetic approaches to construction of designed proteins have primarily relied on the known secondary structure-forming propensities of amino acids, gleaned from analysis of known protein structures, to generate specific secondary structures, which can be subsequently assembled into three dimensionally well defined structural motifs under the influence of hydrophobic driving forces. Thus, a large number of de novo designed proteins employ specific patterning of polar and nonpolar amino acids in their sequences. A different approach to synthetic protein design involves stabilization of specific secondary structures by the use of stereochemically constrained non-protein amino acids or by use of synthetic templates, which permits nucleation of helices, or beta-sheets. Using non-protein amino acids as strong conformational determinants, a modular approach to synthetic proteins can be envisaged. In this strategy, prefabricated modules of previously well characterized secondary structures, like helices and beta-hairpins, are generated and are linked together by suitable linkers. The folding of such proteins are entirely dependent on the enthalpic contributions from intramolecular hydrogen bonds and van der Waals interactions in a weakly interacting solvent. Generation of higher order folding motifs based on this strategy can be termed as a "Meccano set" approach to synthetic protein design. Beta hairpins and multi stranded structures can be readily generated in synthetic sequences by incoporating DPro-Xxx turn segments. Helices, on the other hand, can be easily constructed by making use of the alpha, alpha-dialkylated amino acids, like alpha-aminoisobutyric acid (Aib).
Keywords: Synthetic Peptide, Protein Design, Helix, β-Sheet, and Folding
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