A molecular design algorithm for peptide ligands has been developed. This design algorithm utilizes the structural parameterization of the energetics as a way of identifying the conformation with the minimum energy. The implementation of the algorithm involves two non-mutually exclusive procedures for computer mutagenesis of a lead peptide. Mutations in sequence by replacing side chains at existing positions in the peptide, and alteration of peptide chain length by addition or deletion of amino acids. Once the mutation is made it is necessary to sample the ensemble of possible conformations and evaluate the energy and corresponding probability of each conformation. The probability of a single peptide conformation, defined by a specific set of side chain and backbone coordinates, is dictated by a Gibbs energy function or Gibbs potential, Gef, specified by the enthalpy of intra and intermolecular peptide/protein interactions plus the enthalpy and entropy of solvation. Gef is a function of the side chain and backbone torsional angles. By definition, the conformational entropy of the peptide itself does not enter into the equation. Gef is the Gibbs energy function of a single conformation and should not be confused with the Gibbs energy of binding which includes all permissible conformations. The Gibbs potential function, Gef, is used to identify the most probable conformation of a side chain or backbone.
Showing the most recent 10 out of 86 publications
