Volume 11 Number 34 14 September 2020 Pages 9031–9326 Chemical Science rsc.li/chemical-science ISSN 2041-6539 PERSPECTIVE Rainer Herges Molecular assemblers: molecular machines performing chemical synthesis Chemical Science View Article Online PERSPECTIVE View Journal | View Issue Molecular assemblers: molecular machines performing chemical synthesis Cite this: Chem. Sci., 2020, 11,9048 All publication charges for this article Rainer Herges * have been paid for by the Royal Society of Chemistry Molecular assemblers were proposed by K. Eric Drexler in 1986, based on the ideas of R. Feynman. In his (quite lurid) book “Engines of Creation: The Coming Era of Nanotechnology” and follow-up publications Drexler proposes molecular machines capable of positioning reactive molecules with atomic precision and to build larger, more sophisticated structures via mechanosynthesis. These imaginative visions started a hot controversy. The debate culminated in a cover story of Chemical & Engineering News in 2003 (ref. 1) with the key question: “Are molecular assemblers – devices capable of positioning atoms and molecules for precisely defined reactions – possible?” with Drexler as the proponent and Nobelist Richard E. Smalley being the opponent. Smalley raised two major objections: the “fat fingers” and the “sticky fingers” problem. To grab and guide each individual atom the assembler must have many nano- fingers. Smalley argued that there is just not enough room in the nanometer-sized reaction region to Creative Commons Attribution-NonCommercial 3.0 Unported Licence. accommodate all the fingers of all the manipulators necessary to have complete control of the chemistry. The sticky finger issue arises from the problem that .“the atoms of the manipulator hands will adhere to the atom that is being moved. So it will often be impossible to release the building block Received 2nd June 2020 in precisely the right spot.” Smalley concludes that the fat and the sticky finger problems are Accepted 14th July 2020 fundamental and cannot be avoided. While some of the statements of E. Drexler are bold and probably DOI: 10.1039/d0sc03094e not very realistic, his ideas are inspiring and might be a good starting point to assess on how far rsc.li/chemical-science laboratory chemistry has advanced towards real “molecular assemblers” within the last two decades. This article is licensed under a Introduction & overview events. Ribosomes are the most sophisticated, programmable assemblers, and probably far beyond of what we could ever Chemists have been performing reactions with stochastic achieve as chemists. NRPSs are still complex, but their mecha- Open Access Article. Published on 15 July 2020. Downloaded 10/1/2021 4:15:19 PM. ensembles in solution or in the gas phase since the very nisms are suitable as paragons for articial systems. beginning of our eld. Chemical bonds form upon random NRPSs are among the largest enzyme complexes in nature collisions, if the orientations of reaction partners and kinetic (up to 1800 kDa).2 They synthesize a large part of bioactive energies are favourable. Hence, incomplete conversion and side compounds such as antibiotics, siderophores, and immuno- products are usually unavoidable. Notwithstanding advances in suppressants. NRPSs resemble assembly lines, organized in up catalysis, control of reaction parameters, protecting group to 15 subsequent modules. Each module is responsible for strategies and solid-phase synthesis, natural product synthesis performing a specic reaction (condensation, adenylation, thi- in our laboratories has never reached the level of molecular olation, epimerisation, methylation, Claisen ester condensa- assemblers in nature. Life has optimized chemical synthesis in tion, oxidation etc.) and for adding a building block to the a completely different manner and it would not exist based on growing chain (Fig. 1). Each module consists of at least three conventional stochastic chemistry. Living organisms perform domains: the A (adenylation) domain selects and activates the reactions in an extremely selective and efficient manner to substrate, the T (peptidyl carrier, thiolation) domain is survive in a competitive environment with limited resources responsible for the transportation and orientation of the and energy supply, using molecular machines for synthesis. substrate and the C (condensation) domain catalyses the reac- tion. Even though the detailed mechanisms are complex, the general synthetic logic is simple. It seems obvious that bioen- Natural paragons gineering NRPSs (adding, removing and substituting domains Ribosomes, non-ribosomal peptide synthases (NRPSs) and or modules) should allow production of many novel bioactive polyketide synthetases (PKSs) are molecular assemblers that compounds. There is major interest in the use of semi-synthetic perform atomically precise movements along a cascade of hybrids or bioengineered NRPSs as molecular assemblers.3 Success, however, to date has been limited. Each condensation Otto-Diels-Institute of Organic Chemistry, Kiel University, 24118 Kiel, Germany. step in NRPS fabricated synthesis is endergonic and driven by E-mail: [email protected] 9048 | Chem. Sci.,2020,11,9048–9055 This journal is © The Royal Society of Chemistry 2020 View Article Online Perspective Chemical Science ATP. ATP is produced from ADP and Pi by a large enzyme about building articial molecular assemblers; however, the complex ATP synthase (>500 000 daltons). ATP synthase also endeavour could still be unrealistically difficult or too expen- perfectly complies with the denition of a molecular machine sive. Therefore, it might be expedient to look at molecular performing chemical synthesis. assemblers in nature and try to systematically reduce their Surprisingly, structurally diverse and functionally different sophistication and complexity to a level achievable with assemblers such as NRPSs, ATP synthase and chaperones,4 as synthetic chemistry. well as a number of further ATP driven molecular synthetic 5 machines, such as ATP driven proteases, and polyketide syn- Towards articial molecular assemblers thases6 have the following 4-stage assembly sequence in The rst three stages of biological assemblers: (1) recognition common: and binding of the reactants, (2) orientation of the reactants (1) recognition and binding of the reactants. and (3) bond formation have been realized in a number of (2) Orientation of the reactants with atomic precision. articial systems. Assemblers that operate in a cyclic fashion (3) Catalyzed bond formation. (stage 4) have not been known until recently. (4) Active (energy consuming) release of the product and repeating the cycle. “ ” The advantages of machine-type syntheses are obvious: the Mechanical control of reactions following the chemical assembler prevents side reactions, and provides chemo-, regio- potential gradient (downhill) and stereoselective synthesis without protecting groups or Hosseini and Lehn8,9 reported a macrocycle catalyzing the chiral auxiliaries. Notwithstanding the numerous examples in formation of pyrophosphate and ATP by hydrolysis of ADP and biology and considerable advances in covalent and supramo- acetyl phosphate. The latter is an activated phosphate and the lecular chemistry, articial, continuously operating assemblers reaction is exergonic. Nevertheless, it demonstrates the power have not been realized so far. Fortunately, there is at least one of supramolecular catalysis. The rst non-continuously oper- Creative Commons Attribution-NonCommercial 3.0 Unported Licence. encouraging argument on Drexler's side. In 1972 the economist ating assemblers were based on DNA architectures and per- Kenneth E. Boulding stated the following: formed multistep organic synthesis by sequential reactions on If something exists, then it must be possible.7 subsequent stations on a DNA track.10–15 (Fig. 2a) Leigh et al. In terms of molecular assemblers Boulding's law would read: used rotaxanes as the assembly line. In a landmark paper, they “If nature is using molecular assemblers for synthesis, chemists reported the sequence-specic synthesis of a tripeptide16–18 should (at least in principle) be able to build and operate arti- (Fig. 2b). cial assemblers in the laboratory”. Biochemical and chemical Recently the same group published a programmable reactions follow similar principles of chemistry and the same molecular machine for stereodivergent synthesis.19 While DNA laws of physics. There should not be a fundamental problem and rotaxane assembly lines are ingenious designs and This article is licensed under a Open Access Article. Published on 15 July 2020. Downloaded 10/1/2021 4:15:19 PM. Fig. 1 A molecular machine performing chemical synthesis: ATP driven formation of an amide bond in NRPSs. (1) Recognition, activation and binding of a building block, (2) precise orientation of the reactants, (3) catalysed bond formation, and (4) repeating cycles, growing chain and product release. This journal is © The Royal Society of Chemistry 2020 Chem. Sci.,2020,11,9048–9055 | 9049 View Article Online Chemical Science Perspective Fig. 2 (a) DNA and (b) rotaxane based assembly. Creative Commons Attribution-NonCommercial 3.0 Unported Licence. impressive examples of the power of modern synthetic and a light driven information and energy ratchet has been realized supramolecular chemistry, they suffer from the disadvantage by Credi et al.28 Another category of endergonic processes driven that the information is read in a destructive manner. There is no by external energy sources