A literature survey and theoretical calculations have been applied to explore bilateral symmetry in natural product systems. Molecular bilateral symmetry is defined to include C(2) (sigma plane or axis), C(s)(), and C(2)(v)() point groups in molecules. Natural products that possess chirality in the form of C(2)-axes or sigma planes of symmetry are present in higher proportions (69%) compared to molecules bearing achiral C(s)() or C(2)(v)() point groups (14% and 16%, respectively). Density functional theoretical and semiempirical calculations indicate that the dimers 3,3'-dibromo-5,5'-[N-(2-(3-bromo-4-hydroxyphenyl)ethyl)-2-hydroxyiminoacetamide]biphenyl-2,2'-diol (1), (S,S)-1,2-bis(2-amino-3H-imidazol-4-yl)-(R,R)-3,4-bis(1H-pyrrole-2-amido)cyclobutane (2), 2-oxo-dimethyl-1,3-bis(3,4-dibromobenzene-1,2-diol) (11), 1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (12), and bis(5-isopropyl-8-methylazulene)methane (13) evolve more energy per connecting bond than the corresponding trimers or tetramers would. This we propose is a guiding parameter that may adjust molecule growth. The corresponding trimers, tetramers, or higher oligomers of 1, 2, and 11-13 appear to represent "missing" compounds in nature. Natural products 1, 2, and 11-13, having 3-fold and higher levels of symmetry, would founder on the lack of a facile method of synthesis and on the prohibitively high-energy costs caused by steric crowding at their core.

This paper examines ring size patterns of natural product macrocycles. Evidence is presented that natural macrocycles containing 14-, 16-, and 18-membered rings are of frequent occurrence based on a data mining study. The results raise a question about the limited diversity of macrocycle ring sizes and the nature of the constraints that may cause them. The data suggest that the preference bears no relationship to the odd-even frequency in natural fatty acids. The trends reported here, along with those reported previously (Wessjohann et al. (2005) Mol Divers 9:171), may be generalized to better understand the possible structure preferences of natural macrocycles.

We propose a mechanism that bilateral symmetry yields an entropic advantage for enzyme recognition. We suggest that bilateral symmetry may be a guiding principle used by nature to produce some particularly effective receptor-ligand interactions. An essential result is that bilateral symmetry is common among enzyme inhibitors, which coupled with an enhanced bond energy that connects dimer molecules compared to a reduced bond energy profile for higher oligomers provides a clue to explain the abundance of bilaterally symmetrical molecules found in Nature. Keywords Molecular bilateral symmetry . Enzyme recognition . Receptor-ligand interactionsRecent interest has focused on natural product bilateral symmetry and the prediction of selectivity of dimeric molecules by density functional theory (DFT) and semiempirical calculations [1]. It has been shown that bilateral symmetry [defined as including C 2 (sigma mirror or rotation axis), C s , and C 2v point groups in molecules] is present in a number of natural product structures. Dimeric natural products were found to evolve more energy per connection than the corresponding trimers or tetramers. The assumption of maximization of interaction energy suggests the corollary