Rational design of type-IA receptor-derived cyclic peptides to target human bone morphogenic protein 2.

Human bone morphogenetic protein 2 (BMP2) is a bone-growth regulatory factor involved in the formation of bone and cartilage, and has been recogn ized as an attractive therapeutic target for a variety of bone diseases and defects. Here, we report successful design of a head-to-tail cyclic peptide based on crystal structure to target BMP2. Computational alanine scanning identifies two hotspot regions at the crystal complex interface of BMP2 with its type-IA receptor; promising one is stripped from the interface to derive a linear self-inhibitory peptide RPS2 that covers residues 78-94 of the receptor protein. Dynamics simulation and energetics analysis reveal that the peptide is highly flexible in isolated state and cannot spontaneously bind to BMP2. The RPS2 peptide is further extended from its N- and C-termini until reaching two spatially vicinal residues 74 and 98 in the crystal structure of intact BMP2-receptor complex system, consequently resulting in a longer peptide RPS2, which is then cyclized in a head-to-tail manner to obtain its cyclic counterpart cycRPS2. Computational analysis suggests that the cyclic peptide can well maintain in a conformation similar with its active conformation in complex crystal structure, exhibiting a smaller disorder and a larger potency than its linear counterpart. Further assays confirm that the two linear peptides RPS2 and RPS2are nonbinders of BMP2, whereas, as designed, the cyclic peptide cycRPS2 can bind to BMP2 with a moderate affinity. The cyclic peptide is expected as a lead molecular entity to develop new and potent peptide-based drugs for BMP2-targeted therapy.