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.
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 Calpha-Cbeta 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 < or = 3.0 A were classified into the same known canonical reverse-turn Calpha-Cbeta 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 Calpha-Cbeta 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 Calpha-Cbeta bonds in the reverse turn.
Arbor
Sage
S
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA. sagearbor@gmail.com
Marshall
Garland R
GR
D003198:Computer Simulation; D030562:Databases, Protein; D008956:Models, Chemical; D009842:Oligopeptides / Q000737:chemistry*; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000737:chemistry*; D011487:Protein Conformation; D013816:Thermodynamics
D009842:Oligopeptides; D019151:Peptide Library; D010456:Peptides, Cyclic
J Med Chem. 2006 Jan 12;49(1):111-24
16392797
J Comput Aided Mol Des. 2005 Aug;19(8):551-66
16328857
Angew Chem Int Ed Engl. 2002 Aug 16;41(16):2879-90
12203413
Annu Rev Biochem. 1992;61:387-418
1497316
Curr Med Chem. 1998 Feb;5(1):29-62
9481033
Biopolymers. 1996;40(1):45-83
8541448
Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8189-93
8710845
Biopolymers. 2008;90(3):384-93
17941003
J Med Chem. 2005 Dec 1;48(24):7667-74
16302807
Proc Natl Acad Sci U S A. 1994 May 24;91(11):4708-12
8197123
J Comput Aided Mol Des. 2002 Aug-Sep;16(8-9):585-600
12602952
Proteins. 1993 Mar;15(3):235-51
8456095
J Comput Aided Mol Des. 1993 Feb;7(1):3-22
8473917
Chem Rev. 2005 Mar;105(3):793-826
15755077
Org Lett. 2007 Jan 4;9(1):101-4
17192095
Protein Eng. 2003 Jan;16(1):65-72
12646694
Drug Discov Today. 2003 Aug 1;8(15):681-91
12927511
Chem Rev. 2003 Mar;103(3):893-930
12630855
Adv Protein Chem. 1985;37:1-109
2865874
Protein Sci. 1993 Jul;2(7):1085-91
8358291