PRO-LIGAND - AN APPROACH TO DE-NOVO MOLECULAR DESIGN .6. FLEXIBLE FITTING IN THE DESIGN OF PEPTIDES

This paper describes the further development of the functionality of o ur in-house de novo design program, PRO_LIGAND. In particular, attenti on is focussed on the implementation and validation of the 'directed t weak' method for the construction of conformationally flexible molecul es, such as peptides, from molecular fragments. This flexible fitting method is compared to the original method based on libraries of presto red conformations for each fragment. It is shown that the directed twe ak method produces results of comparable quality, with significant tim e savings. By removing the need to generate a set of representative co nformers for any new library fragment, the flexible fitting method inc reases the speed and simplicity with which new fragments can be includ ed in a fragment library and also reduces the disk space required for library storage. A further improvement to the molecular construction p rocess within PRO_LIGAND is the inclusion of a constrained minimisatio n procedure which relaxes fragments onto the design model and can be u sed to reject highly strained structures during the structure generati on phase. This relaxation is shown to be very useful in simple test ca ses, but restricts diversity for more realistic examples. The advantag es and disadvantages of these additions to the PRO_LIGAND methodology are illustrated by three examples: similar design to an alpha helix re gion of dihydrofolate reductase, complementary design to the active si te of HIV-1 protease and similar design to an epitope region of lysozy me.