Generic shapes for the conformation analysis of macrocyclic structures

Abstract

Abstract A new algorithm for the systematic generation of conformations of macrocyclic systems is presented. The procedure is based on the concept of generic shapes that are found in such structures. These shapes are characterized by a selection of harmonics which occur in an approximate Fourier representation of the atomic coordinates of the rings. Following a fixed protocol, a limited set of in‐plane and out‐of‐plane circular harmonics is used to define an ensemble of generic ring shapes. These generic shapes are used as start structures for energy minimizations by a given force‐field method. To account for the possibility of having several final conformations originating from the same generic shape, the corresponding initial structure is taken several times and subjected to a randomization step before minimization. The resulting conformations that fall within a preset low‐energy band are collected and screened for duplicates and enantiomers. The efficiency of this procedure (ratio between the number of accepted conformations and the total number of energy minimizations) depends on the flexibility of the macrocyclic system. The efficiency is generally quite high for very flexible rings. According to the proposed protocol, the number of generic shapes used as start structures grows as the square of N (ln N ), where N is the ring size. The algorithm lends itself to conformational analyses of medium‐size and large rings as well as of loops spanned between fixed structural units.