Molecular modeling of the interaction of neurotrophins with the p75NTR common neurotrophin receptor

Neurotrophins are a family of proteins with pleiotropic effects mediated by two distinct receptor types, namely the trk family and the common neurotrophin receptor p75(NTR). Binding of four mammalian neurotrophins, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5), to p75(NTR) is studied by large scale molecular dynamics simulations using CHARMM force field. Geometric match of neurotrophin/receptor binding domains in the complexes is evaluated by the Lawrence & Colman's shape complementarity statistic Sc. The model of neurotrophin/receptor interactions suggests that the receptor binding domains of neurotrophins (loops I and IV) are geometrically and electrostatically complementary to a putative binding site of p75(NTR), formed by the second and part of the third cysteine-rich domains. All charged residues within the loops I and IV of the neurotrophins, previously determined as being critical for p75(NTR) binding, directly participate in receptor binding in the framework of the model. Principal residues of the binding site of p75(NTR) include Asp(47), Lys(56), Asp(75), Asp(76) Asp(88) and Glu(89). The additional involvement of Arg(80) and Glu(53) is specific for NGF and BDNF, respectively, and Glu(73) participates in binding with NT-3 and NT-4/5. The model developed has utility in computer-aided molecular design.