Biodynamers: Self-Organization-Driven Formation of Doubly Dynamic Proteoids Anna K. H Hirsch, †,§ Eric Buhler, ‡ and Jean-Marie Lehn* ,† † Institut de Science et d’Inge ́ nierie Supramole ́ culaires (ISIS), Universite ́ de Strasbourg, 8, alle ́ e Gaspard Monge, 67000 Strasbourg, France ‡ Laboratoire Matie ̀ re et Syste ̀ mes Complexes (MSC), UMR CNRS 7057, Bâ timent Condorcet, Universite ́ Paris Diderot-Paris 7, 75205 Paris cedex 13, France * S Supporting Information ABSTRACT: Polypeptide-type dynamic biopolymers (bio- dynamers) have been generated by polycondensation via acylhydrazone and imine formation of amino-acid-derived components that polymerize driven by self-organization. They have been characterized as globular particles, reminiscent of folded proteins, by cryo-TEM, LS, DOSY NMR, and SANS studies. The reversible polymers obtained show remarkably low dispersity and feature double covalent dynamics allowing for fine-tuning of both exchange and incorporation processes through pH control. In the course of build-up, they perform a selection of the most suitable building block, as indicated by the preferential incorporation of the more hydrophobic amino-acid component with increased rate and higher molecular weight of the polymer formed. The system described displays nucleation- elongation behavior driven by hydrophobic effects and represents a model for the operation of adaptation processes in the evolution of complex matter. ■ INTRODUCTION Dynamers, dynamic polymers, result from the application of constitutionally dynamic chemistry (CDC) 1 to polymer science. 2 They are characterized by the linkage of monomers by reversible connections, be they of supramolecular/non- covalent 1,2 or molecular/covalent 1-3 nature. If components of a biological type are used, dynamic analogues of natural macromolecules, or biodynamers, are generated that combine the benefits of constitutional dynamics with those of bio- logically significant residues. 4 As a result of their inherently dynamic nature, dynamers can undergo changes in their length, sequence, and constitution by monomer incorporation and exchange in response to external stimuli such as temperature or pH. The resulting materials may display novel properties and have great potential as stimulus-responsive or “smart” materials. 5 Given such promising perspectives, the development of dynamic analogues of the different biological macro- molecules is highly desirable, as recently exemplified for dynamic analogues of polysaccharides 4a-c and of nucleic acids. 4d Mimicking proteins is of particular interest given the prospect such systems should offer in terms of using the primary sequence to encode a well-defined three-dimensional structure. In addition to allowing for control of the structure of the biodynamers obtained, examination of such behavior deserves closer scrutiny in the light of postulates stating that protein folding has driven primary sequence development. 6 Investigating how supramolecular and medium effects, especially hydrophobic effects as in protein folding, can be exploited as driving force will be of fundamental importance, given that all reactions are to be carried out in an aqueous environment. Such factors also direct the formation of complex supramolecular assemblies of great interest in materials and biological sciences, in particular as biomaterials. 7-10 Along these lines, we report here the design and synthesis of dynamic proteoidic polymers, their characterization by several physical methods as well as some of their mechanistic and dynamic features. 11 ■ RESULTS AND DISCUSSION Design of Dynamic Proteoids. The formation of imine- type bonds 1-4 has been widely implemented in CDC as a reversible condensation reaction and is of broad applicability both in the fields of dynamers and biodynamers. 1-4 Depending on the type of amino and carbonyl groups used, the resulting dynamers have different stabilities and are formed more or less readily because of the different reactivities of different imine- type bonds, e.g., those of true imines and those of acylhydrazones. 12 Dynamic polymers generated from two different types of imine bonds offer particularly interesting prospects. Such polymers may be described as presenting double covalent dynamics in view of the occurrence of two different condensation reactions (constitutional dynamics); in Received: October 21, 2011 Published: February 2, 2012 Article pubs.acs.org/JACS © 2012 American Chemical Society 4177 dx.doi.org/10.1021/ja2099134 | J. Am. Chem. Soc. 2012, 134, 4177-4183