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Engineering cyclic tetrapeptides containing chimeric amino acids as preferred reverse-turn scaffolds
1Center for Computational Biology and Department of Biochemistry and Molecular Biophysics, Washington University, St. Louis, Missouri 63110, USA.
Journal of Medicinal Chemistry
|January 6, 2006
Summary
Cyclic tetrapeptides (CTPs) offer minimalist scaffolds for protein reverse turns. These CTPs, especially those with heterochiral dipeptides, can effectively mimic protein reverse-turn structures and allow for diverse molecular designs.
Area of Science:
- Biochemistry
- Computational Chemistry
- Structural Biology
Background:
- Reverse turns are crucial protein motifs involved in molecular recognition.
- Constraining peptides into reverse-turn conformations is essential for studying their function.
- Cyclic tetrapeptides (CTPs) offer a promising approach as minimalist scaffolds.
Purpose of the Study:
- To evaluate CTPs as minimalist scaffolds for reverse-turn conformations.
- To investigate the conformational stability and properties of CTPs using computational methods.
- To explore the potential of CTPs for designing molecules to probe biological receptors.
Main Methods:
- Density functional theory (DFT) calculations were employed.
- Molecular dynamics (MD) simulations were performed.
- Principal component analysis (PCA) was used to analyze C(alpha)-C(beta) vector orientations.
Main Results:
- The all-trans amide conformer was most stable in vacuo; cis-trans-cis-trans (ctct) and trans-cis-trans-cis (tctc) conformers were favored in water.
- Conformational interconversions were limited due to ring constraints.
- CTP scaffolds effectively mimicked most protein reverse-turn structures (RMSD ~0.5 Å).
- Functionalization of proline rings offers extensive design diversity.
Conclusions:
- CTPs, particularly those incorporating heterochiral dipeptides, serve as effective minimalist scaffolds for reverse turns.
- Substitutions on proline rings allow for selective stabilization of different conformations.
- The structural diversity of CTPs can be enhanced by incorporating proline analogues.
- CTPs hold significant potential for developing novel molecular probes.
