Professor Ivan Huc (Department of Pharmacy, LMU) studies aspects of the self-organization processes that enable macromolecules to adopt defined folded shapes. The molecular structures found in nature provide him with models, whose properties he tries to reproduce in the laboratory with non-natural molecules that are neither proteins, nucleic acids or sugar-like. More specifically, he uses the tools of synthetic chemistry to elucidate the underlying principles of self-organization -- by constructing molecules that are expressly designed to fold into predetermined shapes. Beginning with monomers that his group has developed, he sets out to produce what he calls 'foldamers', by assembling the monomers one by one to generate a folded macromolecule.

Structures with low degrees of symmetry

"The normal way to get the complex structure of proteins is to use different types of monomers, called amino acids," as Huc reports. "And the normal method to connect different amino acids in the the correct order is to link them one by one." The sequence of amino acids contains the folding information that allows different protein sequences to fold in different ways.

"But we discovered something unexpected and spectacular," comments Huc. He and his colleagues in Munich, Groningen, Bordeaux and Berlin used organic, sulfur-containing monomers to spontaneously get cyclic macromolecules with a complex shape, as illustrated by their low degree of symmetry, without requiring a specific sequence. The macromolecules self-synthesize -- no further conditions are necessary. "We only put one monomer type in a flask and wait," Huc says. "This is typical for a polymerization reaction, but polymers from a single monomer usually don´t adopt complex shapes and don't stop growing at a precise chain length."

To further control the reaction, the scientists also used either a small guest molecule or a metal ion. The regulator binds within the growing macromolecule and causes monomers to arrange themselves around it. By choosing a regulator with the appropriate characteristics, the authors of the new study were able to produce structures with a predetermined number of subunits. The cyclic macromolecules exhibited low levels of symmetry. Some consisted of either 13, 17 or 23 subunits. Since 13, 17 and 23 are prime numbers, the corresponding folded shapes exhibit low degrees of symmetry.

A model for biological and industrial processes

Interest in the elucidation of such mechanisms is not restricted to the realm of basic research. Huc and his colleagues hope that their approach will lead to the fabrication of designer plastics. Conventional polymers usually consist of mixtures of molecules that vary in length (i.e. the number of monomers they contain). This heterogeneity has an impact on their physical properties. Hence, the ability to synthesize polymer chains of an exact length and/or geometry is expected to lead to materials with novel and interesting behaviors.

Furthermore, foldamers like those that have now been synthesized show close structural resemblances to biopolymers. They therefore offer an ideal model system in which to study the properties of proteins. Every protein is made up of a defined linear (i.e. unbranched) sequence of amino acids, which constitutes its 'primary structure'. But most amino-acid chains fold into local substructures such as helically coiled stretches, or parallel strands that can form sheets. These units represent the protein's secondary structure. The term 'tertiary structure' is applied to the fully folded single chain. This in turn can interact with other chains to form a functional unit or quaternary structure.

Huc's ultimate goal is to mimic complex biological mechanisms using structurally defined, synthetic precursors. He wants to understand how, for example, enzymes fold into the correct, biologically active conformation following their synthesis in cells. Molecules whose properties can be precisely controlled in the laboratory provide ideal models with which to work out the answers and perhaps to go beyond enzymes themselves.

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Materials provided by Ludwig-Maximilians-Universität München. Note: Content may be edited for style and length.

Journal Reference:

1. Charalampos G. Pappas, Pradeep K. Mandal, Bin Liu, Brice Kauffmann, Xiaoming Miao, Dávid Komáromy, Waldemar Hoffmann, Christian Manz, Rayoon Chang, Kai Liu, Kevin Pagel, Ivan Huc, Sijbren Otto. Emergence of low-symmetry foldamers from single monomers. Nature Chemistry, 2020; 12 (12): 1180 DOI: 10.1038/s41557-020-00565-2