Bioinorganic Chemistry: A Field Where Biomimetism and Bioinspiration Are Central

Biomimicry (1) has emerged as a highly heuristic approach in many fields: why not learn from the strategies selected by Nature over millions of years of evolution and put them to use? At the macroscopic level, we can observe Nature and learn from the spider’s web spreading on grass to create a light and resistant biomimetic roof, such as that of the stadium built by Otto Frei for the 1972 Olympic Games in Munich. We can also take inspiration from the tentacles of octopuses to create efficient soft robots (2) that contrast with the way we usually think of robots as hard─remember C3-PO in the epical movie “Star Wars”. At the molecular level, bioinorganic chemists, interested in metallobiomolecules, can try to mimic the metallic active site of metalloenzymes to gain information on these systems. This may spark inspiration for designing efficient catalysts. Biomimetism or biomimicry and bioinspiration are frequently used, and the article by Engbers et al. (3) discusses these approaches in bioinorganic chemistry with several relevant case studies. As stated by Lippard in 2006, “The [···] approaches [in synthetic modelling chemistry] are either biomimetic, in which the constructs are as faithful as possible to the coordinating atoms and structures found in nature, or bioinspired, in which achieving the function under ambient conditions is the goal, irrespective of the ligands.” (4) But “as faithful as possible” makes it difficult to draw the line. Indeed, the distinction between bioinspired and biomimetic is often a matter of interpretation. To “biomimic” a metalloprotein or a metalloenzyme, should we reproduce the first coordination sphere, the second coordination sphere, the spin state of the metal complex? Other features of the protein, further away from the second sphere, such as important networks of H-bonds, charged funnels to attract a substrate or narrow access channel selecting substrates according to size and orienting them, etc., may also be important to the activity. (5) Finally, if we stick to this definition, are not we doomed to reproduce the full biological system to make it “truly” biomimetic? An important aspect seems to be the intention of the researchers who, if well informed, are probably in the best position to label their work. The intention is usually divided into two types: to provide some additional knowledge (descriptive, informative perspective), which is by nature biomimetic, and to develop new active systems (functional perspective), which are clearly in a continuum from biomimetic to bioinspired (Figure 1). Figure 1. Research in bioinorganic chemistry and informative and functional perspectives. Distinction between biomimetic and bioinspired chemistry. 1. At the basis of the informative/descriptive approach is the synthetic chemical modeling. Libraries of synthetic low molecular weight (LMW) can be easily generated. They can help to identify spectral signatures or specific structural and functional features in metal complexes depending on the redox or spin state of the metal ion and on the coordinating Lewis bases, such as their type (N, O, S, charge), number, or geometry of the coordination sphere. In the case of spectroscopic mimics, (6) those systematic studies, which were very active from the late 1980s to 2000, have provided the scientific community with useful information on the spectra expected for electronic absorption (UV–vis), vibrational (IR/Raman), Mössbauer, X-ray fluorescence spectroscopies, etc. The repertoires for such fingerprintings continue to grow with more recent main additions related to the characterization of transient species (M adduct such as M═O (7) or M–OO, (8) for instance). Indeed, one asset of these LMW complexes for identification of the signature of transient species lies in that they can be manipulated in organic solvents, which can be cooled at low temperatures while remaining liquid. Transient intermediates can thus be formed and kept at low temperature long enough to be analyzed, leading to the identification of spectroscopic features and the building of a rationale for the parameters controlling them. Back to biological systems, they can be looked for in biomolecule intermediates, either as purified samples and freeze quenched or even directly in cells. (9) Clearly, this informative approach, with the so-called “synthetic analogues” of metalloproteins’ active sites, has contributed significantly to our understanding of the metalloenzymes’ functioning. (5,10,11) 2. The functional approach involves the usage of what has been understood of the structure and mechanism to design a functional molecular system, most often simpler than the enzyme. This can be achieved by being as close as possible to the natural system for the parameters we think of as essential. This asset of such a molecular system is to be (easily) synthesized and played with like a “molecular Lego-set” to control a function. This approach, based on the structural and mechanistic knowledge on metalloenzymes, implies forging chemical intuitions by inferring from what we have grasped of a mechanism selected in a biological molecule in the slow evolutionary Darwinian process. This bioinspired process, mainly iterative, (10,12) takes us away from a biological system that serves as an initial model, to go elsewhere to what is circumscribed by biomimetic reproduction. Armed with this new dimension of reflection, the bioinorganic chemist can then, in the words of Diekmann et al., (13) open their toolbox (organic, inorganic, biochemical, and theoretical) to construct new entities with controlled reactivity, whether they be efficient synthetic catalysts, materials, or modified proteins with hijacked activity. 3. Why bother? What motivates biomimetic/bioinspired research is the fact that the activities of metalloenzymes─like those of enzymes in general─are often of high added value, with efficient and elegant solutions carved by evolution for key processes: activation of small molecules (O₂, N₂, etc.), reduction of CO₂, functionalization of alkanes, production of dihydrogen, dioxygen, or ammonia, energy conversion, control of oxidative stress, etc. Chemists can use these examples as a source of inspiration to design metallic compounds or materials, mainly catalysts, with controlled properties of industrial or pharmaceutical interest. This is of paramount importance to society because biology uses available, abundant metal ions, and there is a need to switch from the use of rare noble-metal ions to less precious ones due to the impending scarcity of metal ions. 4. One simple example. To illustrate this and perhaps make my point clearer, the following example (14) will be used and deals with the design of superoxide dismutase (SOD) mimics. Metal-based SOD-like activity is controlled mainly by the redox states of metal ions. Despite the intrinsic redox properties of the metal ions involved [Fe(III)/Fe(II), Mn(III)/Mn(II), Cu(II)/Cu(I), and Ni(III)/Ni(II)] spanning a wide range of potentials, all SODs (Fe, Mn, Cu, Ni) exhibit similar redox potentials, optimal to superoxide dismutation. Inspired by the bipyramidal structure MnHis3Asp1 of the active site of MnSOD (Figure 2), we have designed a series of complexes MnN3O with O from a carboxylato, as in the Asp (aspartate), and varied the ligand structure away from that of the enzymatic active site. In place of the tripodal amine chosen initially to emulate the biomimetic trigonal structure, a phenolato was used in lieu of a carboxylato and a 1,2-diaminoethane has been introduced. This resulted in a more stable Mn(II) complex (higher denticity) with a redox potential close to the optimal value for superoxide dismutation and a position for modularity (secondary amine). Starting from the structure of the active site of MnSOD, we were slightly moving away from the bipyramidal MnHis3Asp1 to obtain a more active catalyst. Figure 2. SOD mimics bioinspired from MnSOD, a continuum between biomimetic and bioinspired chemistry: starting from the structure of the active site (a), biomimetic ligands (b) reproducing the main features of the first coordination sphere [for bis(imidazole) glycinate (BIG): 2 Im, 1N, 1 COO^─, trigonal structure], gradually moving away (the carboxylato changed to phenolato for a better redox potential match in phenolimidazole (PI); the tripodal amine changed to 1,2-diaminoethane for a higher denticity and a position for conjugation in en for 1,2-diaminoethane (enPI2). (a) Active site of the human mitochondrial MnSOD from Borgstahl et al. Cell 1992, 171, 120. (b and c) Data from refs (15)– () (17) (E_a: anodic peak). See ref (14) from more details. Scientific work begins with a foundation upon which to build and elaborate away; in the case of SOD mimics, the structure of the MnSOD active site provided a suitable starting point (essentially biomimetic), while knowledge of the optimal redox potential provided the impetus to modify the structure for improvement. In conclusion, inspired by the Nobel lecture of Feringa, (18) we take the example of flight. Human beings have always been eager to fly, and watching birds has been a strong motivation. It was important to discover how birds fly, but, clearly, their way of flying requires a tremendous amount of energy and complex movement of the wings that is not easy to reproduce. However, they also glide efficiently. Therefore, another way of decomposing their flight is to associate gliding with a propeller and eventually a propulsion motor. Planes do not fly in a way biomimetic to birds, but birds’ flight has motivated and inspired generations of inventors and engineers, leading to aircraft technology and eventually, at a different scale, molecular motors that can actuate within biological systems, for instance, for the light-induced delivery of therapeutic agents, as designed by Feringa. (19,20) We hope that this commentary, linked to Engbers’ article, (3) will help researchers, who are once again in the best position to identify their intentions, to define their research in the continuum between biomimetic to bioinspired. The author acknowledges the Ecole Normale Supérieure (ENS-PSL), CNRS, PSL university, Sorbonne University, Paris-Saclay University, ENS-Paris Saclay, Agence nationale de la recherche (ANR), Fédération pour la recherche médicale (FRM), association François Aupetit, CEFIPRA and other bodies for funding their work. She acknowledges her colleagues, from her laboratory at the Ecole normale supérieure (https://ens-bic.fr/) and worldwide, for useful discussions on this topic. This article references 20 other publications. This article has not yet been cited by other publications.