Biomimetic design of platelet adhesion inhibitors to block integrin α2β1-collagen interactions: I. Construction of an affinity binding model.
Platelet adhesion on a collagen surface through integrin α2β1 has been proven to be significant for the formation of arterial thrombus. However, the molecular determinants mediating the integrin-collagen complex remain unclear. In the present study, the dynamics of integrin-collagen binding and molecular interactions were investigated using molecular dynamics (MD) simulations and molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) analysis. Hydrophobic interaction is identified as the major driving force for the formation of the integrin-collagen complex. On the basis of the MD simulation and MM-PBSA results, an affinity binding model (ABM) of integrin for collagen is constructed; it is composed of five residues, including Y157, N154, S155, R288, and L220. The ABM has been proven to capture the major binding motif contributing 84.8% of the total binding free energy. On the basis of the ABM, we expect to establish a biomimetic design strategy of platelet adhesion inhibitors, which would be beneficial for the development of potent peptide-based drugs for thrombotic diseases.
Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University , Tianjin 300072, People's Republic of China.
Lin
L
Zhang
Yan
Y
Sun
D032701:Biomimetics / Q000379:methods*; D001798:Blood Proteins / Q000737:chemistry*; D003094:Collagen / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D038982:Integrin alpha2beta1 / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D011485:Protein Binding
D001798:Blood Proteins; D038982:Integrin alpha2beta1; C024875:platelet adhesion inhibitor; D003094:Collagen