A virtual library of constrained cyclic tetrapeptides that mimics all four side-chain orientations for over half the reverse turns in the protein data bank
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Reverse turns are often recognition sites for protein/protein interactions and, therefore, valuable potential targets for determining recognition motifs in development of potential therapeutics. A virtual combinatorial library of cyclic tetrapeptides (CTPs) was generated and the bonds in the low-energy structures were overlapped with canonical reverse-turn Cα–Cβ bonds (Tran et al., J Comput Aided Mol Des 19(8):551–566, 2005) to determine the utility of CTPs as reverse-turn peptidomimetics. All reverse turns in the Protein Data Bank (PDB) with a crystal structures resolution ≤3.0 Å were classified into the same known canonical reverse-turn Cα–Cβ bond clusters (Tran et al., J Comput Aided Mol Des 19(8):551–566, 2005). CTP reverse-turn mimics were compiled that mimicked both the relative orientations of three of the four as well as all four Cα–Cβ bonds in the reverse turns of the PDB. 54% of reverse turns represented in the PDB had eight or more CTPs structures that mimicked the orientation of all four of the Cα–Cβ bonds in the reverse turn.
KeywordsCyclic tetrapeptide Reverse turn Mimic Conformational search
This work was funded in part by NIH Grant GM 68460. Sage Arbor acknowledges fellowship support from the Division of Biology and Biological Sciences, Washington University in St. Louis, Kauffman Cancer Research Pathway, and Washington University Center for Computational Biology Pathway.
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