Molecular modelling studies of a nerve growth factor receptor

Using computer simulations, a geometry for the receptor binding site for nerve growth factor (NGF) has been proposed. Variable basis Monte Carlo simulated annealing calculations have been used to ascertain the structures of the complexes of four fully active NGF analogues with the second leucine-rich motif (LRM-2) of trkA, a putative binding site for NGF. The previously suggested bioactive conformation of the amino and carboxyl termini of NGF docks favourably with the receptor defined by the LRM-2 of trkA: only minor conformational changes take place in the NGF analogues upon docking. Extensive intermolecular van der Waals contacts arise from the geometric fit of the NGF binding domain to the LRM-2. Within this receptor environment, five distinct binding areas reveal a highly selective multiple-point NGF-trkA recognition based on hydrophobic, ionic, hydrogen bonding, and van der Waals interactions. Binding specificity is determined primarily by residues Lys100, Asp109, and Phe113 of trkA which bind to conserved NGF residues Asp16, Arg114, Lys115, and Phe7. An explicit atom-level model of the high-affinity NGF receptor is thus developed.Key words: NGF, trkA, leucine-rich motif, protein docking, Alzheimer's disease.