Cyclic tetrapeptides I: The calculated potential energy minima of cyclic tetrapeptides composed of small amino-acid residues

Abstract

Abstract An almost automatic general computational procedure has been devised which enables location of all the low-energy conformations of cyclic peptides containing up to ten or so amino-acid residues. The scale of the computations involved can be considerably reduced if only the global minimum energy conformation is required. The algorithm consists of folding a model of the linear polypeptide chain, with the desired number of residues and arbitrary geometry, into a series of low-energy conformations which correspond to all possible combinations of ‘generators’. The ‘generators’ are pairs of (φ,ψ) torsion angles which indicate the positions of minima in Ramachandran maps for each overlapping dipeptide pair in the target cyclic peptide. Each ‘generator’ has an associated statistical weight which may or may not be subsequently used to screen out cyclic peptide conformations. The folded polypeptide chains so generated are operated on by a ring closure algorithm and a battery of tests to reject sterically unreasonable conformations. Recalcitrant conformations are marked for subsequent examination by a computer graphics system. The geometries of the surviving model conformations are finally optimized by means of a two-stage, Newton-Raphson energy minimization algorithm. Forty such low-energy conformations, including the global minimum, were obtained from 7776 generated conformations of c-Gly4.