Supramolecular Pharmacy
13. Molecular machines and nano/microrobots
Ondřej Jurček
1
30 years of Supramolecular Chemistry
2
host-guest
chemistry
sphere Pd48L96 molecular machines
nanocar
cryptands Mg4L6 cage
blue box
catenane
air-stable P4
inside a cage
nanoparticles
History
3
• 1987 – Award of the Nobel prize for Chemistry to Donald J. Cram, Jean-Marie
Lehn and Charles J. Pedersen "for their development and use of molecules
with structure-specific interactions of high selectivity„
• 1991 – J. Fraser Stoddart introduces rotaxanes
• 1999 – Bernard L. Feringa developed molecular motor
• 2016 – Award of the Nobel prize for Chemistry to Jean-Pierre Sauvage, Sir J.
Fraser Stoddart, Bernard L. Feringa "for the design and synthesis of
molecular machines"
Biological molecular machines
4
• Motor proteins such as myosin (muscle contraction); kinesin (moves cargo inside cells
away from the nucleus along microtubules); and dynein (moves cargo inside cells
towards the nucleus and produces the beating of flagella)
• ATP synthase which harnesses energy from proton gradients across membranes to
drive a turbine-like motion used to synthesize ATP
• DNA polymerases for replicating DNA, RNA polymerases for producing mRNA, or the
ribosome for synthesizing proteins
Ribosome synthesis of protein
Wikipedia
ATP synthase
Artificial Molecular Machines
5
• Machine is a piece of equipment with several moving parts that uses power to do a
particular type of work
• Artificial molecular machine (AMMs) = class of molecules typically described as an
assembly of a discrete number of molecular components intended to produce
mechanical movements in response to specific stimuli
• AMMs require presence of moving parts, the ability to consume energy, and the
ability to perform a task
• AMMs exploit the existing modes of motion in molecules, such as rotation about
single bonds or cis-trans isomerization
• Well-orchestrated symphony of molecular interactions is required to translate
molecular-level motion, which is usually induced on the sub-nanometer level, into
effects that can be measured and used on the micro and macro levels
• A broad range of AMMs has been designed, featuring different properties and
applications; some of these include molecular motors, switches, and logic
gates.
Logic gates
6
• Molecular logic gates work with one or more input signals based on physical or/and
chemical processes and with output signals based on spectroscopic phenomena
Wikipedia: Molecular logic gate
Artificial Molecular Machines
7
• A major starting point for the design of AMMs is to exploit the existing modes of
motion in molecules (light or chemically driven systems)
a) I. Aprahamian ACS Cent. Sci. 2020, 6, 347−358. b) Wikipedia: Molecular machines
• Alignment, order, directionality, tracks, signaling, communication,
compartmentalization, amplification, fuel, regeneration, replication, waste management,
temporal and spatial control, and feedback loops are just a few things to consider in
design
Invention of molecular shuttle by Sir F. Stoddart (1991)
8Stoddart et al. J. Am. Chem. Soc. 1991, 113, 13, 5131–5133
Building upon the assembly of mechanically linked molecules such as catenanes and rotaxanes as developed
by Jean-Pierre Sauvage in the early 1980s
Types of artificial molecular machines
9
• Molecular hinge
• Molecular logic gate
• Molecular necklace
• Molecular propeller
• Molecular shuttle
• Molecular switch
• Molecular tweezers
• Molecular motor
• Nanocar
a) Feringa, Leigh et al. Chem. Soc. Rev. 2017, 46, 2592. b) Wikipedia: Molecular machines.
Types of artificial molecular machines
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• Molecular hinge
• Molecular logic gate
• Molecular necklace
• Molecular propeller
• Molecular shuttle
• Molecular switch
• Molecular tweezers
• Molecular motor
• Nanocar
https://cen.acs.org/articles/95/i23/Molecular-motor-turns-rotor.html
Molecular machines in contact with environment
11Feringa et al. Angew. Chem. Int. Ed. 2016, 55, 10978–10999.
• Manner of providing the interface with environment is by integrating them into bulk
materials (crystals, polymers, or liquid crystals) or by attaching molecular machines to
surfaces
• Crystalline: good to transfer machine‘s work in length (well-defined, ordered, periodic
structure), e.g., incorporating switches such as diarylethenes
• crystal bending
Crystalline molecular machines
12
a) I. Aprahamian ACS Cent. Sci. 2020, 6, 347−358. b) Terao et al. Angew. Chem., Int. Ed. 2012, 51, 901−904.
c) Martinez-Bulit et al. Trends Chem. 2019, vol. 1 (6), 588.
• Drawbacks: crystals are brittle, limited in size and possess narrow structural space
• Using light as trigger – limited penetration depth, which limits the thickness of crystals
to be used (limiting the amount of work)
• Latest development is to incorporate molecular switches, rotors, and motors into MOFs
Molecular photoswitches
13Feringa et al. Nanoscale Adv. 2021, 3, 24–40.
• Azobenzene photoswitches
• the most common used photoswitches (simple
synthesis, photostability, reliability)
• the planar E isomer goes into bulkier Z isomer
• azobenzenes show high quantum yields for both Z/E
and E/Z photoisomerizations, and high photostationary
state ratios
• nearly all the photophysical and photochemical
properties of azobenzenes, in particular quantum yield,
thermal stability of Z-isomer, photostationary state
ratios, excitation wavelengths, can be tuned easily by
introducing appropriate substituents at the azobenzene
core
• well-described in literature
E isomer
Z isomer
Surface mounted molecular machines
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• The surface limits the degrees of freedom available to the molecules, imparts a certain
amount of order on them, and is a convenient way for interfacing and scaling molecular
events with/to the macroscopic world
• Performing work is by using their motion in producing stress on the surface – making
them bend
I. Aprahamian ACS Cent. Sci. 2020, 6, 347−358.
Liquid crystal-polymer molecular machines
15
• Azobenzenes are the most used
• Light-penetration depth issue needs to be addressed as well, but it might be easier to
tackle in polymers using negative photochromic compounds
I. Aprahamian ACS Cent. Sci. 2020, 6, 347−358.
Liquid crystals (LCs)
16
• Properties are between those of conventional liquids and those of solid crystals. For
example, a liquid crystal can flow like a liquid, but its molecules may be oriented in a
common direction as in solid.
Liquid crystal (LC) molecular machines
17a) I. Aprahamian ACS Cent. Sci. 2020, 6, 347−358. b) Nocentini et al. Adv. Optical Mater. 2018, 6, 1800207.
• Ordered soft materials that can amplify, through their long-range self-assembly the
tiniest of molecular motion; i.e., they can be considered as molecular amplifiers
• LC can also translate chiral information
• Challenge is that they are liquid
Molecular machines in polymers
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• Irregular amorphous polymers possess difficulty in imparting synchronized and
ordered motion
• Artificial muscles = α-cyclodextrin (α-CD)
binds stronger with trans-stilbene than
with cis-stilbene, allowing for the lightinduced
sliding of the α-CD ring from the
stilbene station to a poly(ethyleneglycol)
collection area upon trans → cis
isomerization
a) Stoddart et al. Acc. Chem. Res. 2014, 47, 2186−2199. b) I. Aprahamian ACS Cent. Sci. 2020, 6, 347−358.
c) Nocentini et al. Adv. Optical Mater. 2018, 6, 1800207.
Rotaxane-based molecular muscles
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• “daisy chain”, “press”, and “cage” rotaxanes driven by ions, pH, light, solvents, and
redox stimuli
Stoddart et al. Acc. Chem. Res. 2014, 47, 2186−2199.
Molecular machines in polymers
20a) Li et al. Nat. Nanotechnol. 2015, 10, 161−165. b) Foy et al. Nat. Nanotechnol. 2017, 12, 540−545.
Drawbacks
• the switching process in such
materials is slow, resulting in
long irradiation times that lead
to photodegradation, which
restricts the number of
switching cycles that can be
obtained
• polymers only work in
solution, i.e., not as freestanding
dry polymers, which
further encumbers their
practical use
Machines in solution
21I. Aprahamian ACS Cent. Sci. 2020, 6, 347−358.
• Disorder in solution makes it very challenging to extract
useful work from artificial molecular machines (back-andforth
pending according to Brownian motion)
• Artificial cell needs to be designed for artificial molecular
machines to function in solution
• Pump is driving the system out-of-equilibrium by virtue of
kinetically trapping the rings on the collection area, but still
there is no work being produced as there is no way yet to
take advantage of the stored energy
• Possible work, incorporate them into membranes so that the
pump will move the macrocycles from one side of the
membrane to another, thus creating a chemical gradient
Leigh‘s peptide synthesizer
22a) Leigh et al. Chem. Rev. 2015, 115, 10081−10206. b) Leigh et al. Science 2013, 339, 189−193.
Leigh‘s peptide synthesizer
23a) Leigh et al. Chem. Rev. 2015, 115, 10081−10206. b) Leigh et al. Science 2013, 339, 189−193.
Cystic fibrosis
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• Inherited disorder that causes severe damage to the lungs, digestive system
and other organs in the body
• No functional copies (alleles) of the gene cystic fibrosis transmembrane
conductance regulator (CFTR)
• Product of this gene (the CFTR protein) is a chloride ion channel important
in creating sweat, digestive juices, and mucus
https://www.mayoclinic.org/diseases-conditions/cystic-fibrosis/symptoms-causes/syc-20353700
• It regulates flow of Cl- and H2O
• Developing supramolecular chloride
transporters could treat this
disease
Molecular machines in transmembrane transport
25Langton et al. J. Am. Chem. Soc. 2023, https://doi.org/10.1021/jacs.3c08877
• In nature, ion transport is mediated primarily by transmembrane protein channels or
sophisticated biomolecular machine ion pumps and, to a lesser extent, by mobile
carrier (also referred to as ionophores)
Molecular machines in transmembrane transport
26Langton et al. J. Am. Chem. Soc. 2023, https://doi.org/10.1021/jacs.3c08877
Molecular machines in transmembrane transport
27Langton et al. J. Am. Chem. Soc. 2023, https://doi.org/10.1021/jacs.3c08877
Nanorobots
28
• Nanotechnology engineering discipline of designing and building nanorobots with
devices ranging in size from 0.1 to 10 micrometres and constructed of nanoscale or
molecular components
• DNA machines (nubots) - smart biomaterial drug delivery system
• Biohybrids combine biological and synthetic structural elements for biomedical
or robotic applications
• Bacteria-based - use of biological microorganisms, like Escherichia coli or
Salmonella typhimurium (uses a flagellum for propulsion purposes)
• Virus-based - retroviruses can be retrained to attach to cells and replace
DNA (retroviral gene therapy)
• Human cell-based
• Inorganic nanoparticles
a) Pumera et al. Chem 2020, 6, 867–884. b) Nocentini et al. Adv. Optical Mater. 2018, 6, 1800207.
Types of nanorobots
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• Janus particles, sphere-dimers,
hollow geometries, and
nanomotors with intrinsic
asymmetry
a) Pumera et al. Chem 2020, 6, 867–884. b) Nocentini et al. Adv. Optical Mater. 2018, 6, 1800207.
Micro- and nanorobots in precision medicine
30Soto et al. Adv. Sci. 2020, 7, 2002203.
Powering nano-, microrobots
31Soto et al. Adv. Sci. 2020, 7, 2002203.
Drug delivery using micro/nanorobots
32Soto et al. Adv. Sci. 2020, 7, 2002203.
Cell delivery, biopsy, sampling using micro/nanorobots
33Soto et al. Adv. Sci. 2020, 7, 2002203.
Potential Nanorobot Hazards
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• Important prerequisite for successful use is that the nanorobots can evade
the immune systems of the organisms (DNA nanorobots can be
immunogenic)
• Control of nanorobot propulsion and navigation – whether by chemical
propulsion, magnetic fields, sound waves, bioreceptor binding and/or light –
potentially making the nanorobots travel to places in the human body and
elsewhere where they are not supposed to
• Discussions about nanomaterial and nanoparticle definitions shall be led
Arvidsson et al. Environ. Sci.: Nano 2020, 7, 2875.
Sadly, this is the end…
And now the final test!
Thank you for your attention and attendance
during the course!