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Rational Derivation of Osteogenic Peptides from Bone Morphogenetic Protein-2 Knuckle Epitope by Integrating In Silico Analysis and In Vitro Assay
- Source :
- International Journal of Peptide Research and Therapeutics. 27:25-35
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
Abstract
- Human bone morphogenetic protein-2 (BMP2) plays an important role in the development of bone and cartilage, which functions as bone growth factor by interacting with its cognate type-I and type-II receptors (BMPR-I and BMPR-II) through conformational wrist epitope and linear knuckle epitope, respectively. Here, the intermolecular interaction between the BMP2 knuckle epitope and BMPR-II is investigated at structural level, from which a binding hotspot region is identified that is primarily responsible for the epitope recognition by BMPR-II. A KEH peptide covering the hotspot region exhibits a weak binding affinity (Kd = 78.6 ± 13.5 µM) to BMPR-II and a moderate osteogenic activity on human BMSCs (ALP = 135 ± 17% and 164 ± 21% at peptide concentrations 0.01 and 0.1 µg/ml, respectively). Quantitative structure-activity relationship (QSAR) is used to guide the rational optimization of KEH peptide. The strategy focuses on systematic design of the peptide’s non-key residues to derive a series of its promising mutants, which are then evaluated rigorously by using dynamics simulation and energetic analysis. Consequently, totally ten designed peptide mutants are tested in vitro at molecular and cellular levels; most of them are determined to exhibit an increased or comparable affinity/activity relative to the native KEH peptide and knuckle epitope. In particular, the KEH-p7 peptide is found to have a satisfactory profile with Kd = 9.6 ± 1.2 µM and ALP = 178 ± 24% and 235 ± 32% at peptide concentrations 0.01 and 0.1 µg/ml, respectively. Structural analysis reveals a complicated noncovalent network of hydrogen bonds, hydrophobic forces and stacking interactions across the complex interface of BMPR-II with KEH-p7, conferring both stability and specificity to the receptor–peptide interaction.
- Subjects :
- chemistry.chemical_classification
Quantitative structure–activity relationship
010405 organic chemistry
Mutant
Bioengineering
Peptide
01 natural sciences
Biochemistry
Epitope
In vitro
0104 chemical sciences
Analytical Chemistry
Hydrophobic effect
Bone growth factor
chemistry
Drug Discovery
Biophysics
Molecular Medicine
Receptor
Subjects
Details
- ISSN :
- 15733904 and 15733149
- Volume :
- 27
- Database :
- OpenAIRE
- Journal :
- International Journal of Peptide Research and Therapeutics
- Accession number :
- edsair.doi...........5fef94146285562bb94883202fe6c3ef