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 implica ted in Alzheimer's disease, epilepsy, and pain. Although the amino and carboxyl termini enable an NGF's recognition by its TrkA receptor, th eir conformations have not been resolved in recent crystallographic st udies. 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 de termine their bioactive conformation. The complex of the NGF termini s plits into two distinct moieties: a rigid region (residues 9-11 and 11 2'-118') and a flexible loop (residues 1-8). The geometry of the rigid region, which is maintained by electrostatic interaction between Glu( 11) and Arg(118') is conserved in active molecules only. The separatio n of the flexible loop from the rigid region is necessary in order to eliminate an influence of the loop on the biologically active conforma tion of the rigid region. Experimentally observed structure-activity r elationships can be explained using this structural model.