Theoretical Studies on the Bioactive Conformation of Nerve Growth Factor Using VBMCA Novel Variable Basis Monte Carlo Simulated Annealing Algorithm for Peptides

Nerve Growth Factor (NGF) is an important neurotrophic protein implicated in Alzheimer's disease, epilepsy, and pain. Although the amino and carboxyl termini enable an NGF's recognition by its TrkA receptor, their conformations have not been resolved in recent crystallographic studies. Variable Basis Monte Carlo simulated annealing calculations are utilized to study low-energy conformational space of the NGF termini of three highly active and three inactive NGF analogues in order to determine their bioactive conformation. The complex of the NGF termini splits into two distinct moieties:  a rigid region (residues 9-11 and 112‘-118‘) and a flexible loop (residues 1-8). The geometry of the rigid region, which is maintained by electrostatic interaction between Glu¹¹ and Arg^118‘, is conserved in active molecules only. The separation of the flexible loop from the rigid region is necessary in order to eliminate an influence of the loop on the biologically active conformation of the rigid region. Experimentally observed structure−activity relationships can be explained using this structural model.