A MONTE-CARLO METHOD FOR FINDING IMPORTANT LIGAND FRAGMENTS FROM RECEPTOR DATA

A simulated annealing method for finding important ligand fragments is described. At a given temperature, ligand fragments are randomly sele cted and randomly placed within the given receptor cavity, often repla cing or forming bonds with existing ligand fragments. For each new lig and fragment combination, the bonded, nonbonded, polarization and solv ation energies of the new ligand-receptor system are compared to the p revious configuration. Acceptance or rejection of the new system is de cided using the Boltzmann distribution e(-E/kT), where E is the energy difference between the old and new systems, k is the Boltzmann consta nt and T is the temperature. Thus, energetically unfavorable fragment switches are sometimes accepted, sacrificing immediate energy gains in the interest of finding a system with minimum energy. By lowering the temperature, the rate of unfavorable switches decreases and energetic ally favorable combinations become more difficult to change. The proce ss is terminated when the frequency of switches becomes too small. As a test, the method predicted positions and types of important ligand f ragments for neuraminidase that were in accord with the known ligand, sialic acid.