engleski

Computational determination of biologically active motifs of the bone morphogenetic protein precursors

Background and purpose: Bone morphogenetic proteins (BMPs) are potentially useful therapeutic agents for fracture healing and osteoporosis. The optimisation of larger protein molecules is believed to be essential for the development of small molecule therapeutics such as short peptide fragments, small non-peptide molecules or their combinations. Since bioactive peptide motifs are often repetitive sequences of 5-15 amino acids, we conducted a computational investigation of the repetitive sequence motifs of several BMP precursor proteins. BMP precursors were selected since they represent major part of the BMPs, and studies concerning structure-activity relationship in BMPs did not consider a possible role of propeptide parts despite of indications that propeptides of other members of TGF-b family exhibit important regulatory functions. Methods: The aim of our study was to identify repetitive peptide fragments of human BMP precursors and to detect their possible targets according to the Molecular Recognition Theory. Peptide fragments were analysed with respect to the frequency of appearance in different family members. The most probable complementary ligands to the frequent motifs were determined by means of the software SCAN based on the SCA procedure (Symbolic Cantor Algorithm) that represents the optimisation of Molecular Recognition Theory. Results and Conclusion: Computational investigation of the BMP propeptide family extracted links between several BMP propeptides. It is shown that extracted motifs and their complementary targets are in accordance with the experimental data for mature BMP factors. Our results suggest the possibility of BMP precursor optimisation by means of computational methods, and confirm strong structural and functional similarity of several short BMP precursor peptides. Sequences of the most important bioactive human BMP precursors and their complementary peptides are given. The application of the Molecular Recognition Theory may be an useful adjunct to the standard experimental procedures.

BMP precursors; bioactive sequences; osteogenesis; cytoprotection; SCA; SCAN software; molecular recognition

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