Our long term objective is to apply state-of-the-art computer simulation software techniques including molecular dynamics, molecular mechanics and interactive graphics analysis to the understanding of the conformational preferences of biologically active peptides in order to guide and stimulate the design of peptide and non-peptide analogs that block the activity of the peptide at the receptor. Features of the conformational preferences of peptides which we seek to understand through modeling can be mapped for the most part with simple metric descriptors (1). Phase I objectives of this proposal are to develop and implement new conformational analysis algorithms for peptides that utilize a distance matrix (i.e. metric) representation of the molecule; to search the conformational space available to the peptide endothelin using molecular dynamics simulation at elevated temperatures and analyze the conformational space available to this peptide hormone; and to seek collaborative agreements with chemical synthesis/biological testing groups seeking to develop analogs of this peptide. Phase II research will involve investigations of analogs of endothelin, ANF, and other peptides. Commercial goals are to offer analyzed peptide trajectories as a product, and to initiate collaborative agreements in which Biosym Technologies provides modeling expertise leading to the design of peptide and non- peptide analogs of biologically active peptides. Conformational analysis tools developed in these studies will be incorporated into the Biosym Technologies software package for computer aided molecular design.
