The art of building small-Molecular Machines

Hassaan Ahmed

At the start of my journey into the uncharted territory of synthetic chemistry and molecular machines as a young student, I consider it apt to emphasize the joy of discovery that I have experienced through synthetic chemistry. The molecular beauty, structural diversity and, ingenious functions of the machinery of life, which evolved from a remarkably limited repertoire of building blocks, offer a tremendous source of inspiration to the synthetic chemist entering the field of dynamic molecular systems. However, far beyond Nature’s designs, the creative power of synthetic chemistry provides unlimited opportunities to realize our own molecular world as we experience every day with products ranging from drugs to displays that sustain modern society.

In their practice of the art of building small, synthetic chemists have shown amazing successes in the total synthesis of natural products, the design of enantio-selective/orientation-selective catalysts and, the assembly of functional materials, to mention but a few of the developments seen over the past decades. Beyond chemistry’s contemporary frontiers, moving from molecules to dynamic molecular systems, the molecular explorer faces the fundamental challenge of how to control and use motion at the nanoscale. In considering our first successful, albeit primitive, steps in this endeavor of acquiring molecular motion as a scientific community, my thoughts often turn to the Wright brothers and their demonstration of a flying airplane at Kitty Hawk on the 17th of December 1903. Why does mankind need to fly? Why do we need molecular motors or machines? Nobody would have predicted that in the future one would build passenger planes each carrying several 232 Nobel Prizes hundred people at close to the speed of sound between continents. While admiring the elegance of a flying bird, the materials and, flying principle of the entirely artificial airplane are quintessentially distinct from Nature’s designs. Despite the fabulous advances in science and engineering over the past century, manifested most clearly by modern aircraft, we are nevertheless humbled by the realization that we still cannot synthesize a bird, a single cell of the bird, or even one of its complex biological machines. It is fascinating to realize that molecular motors are omnipresent in living systems and key to almost every essential process ranging from transport to cell division, muscle motion, and the generation of the ATP that fuels life processes. In the macroscopic world, it is hard to imagine daily life without our engines and machines, although drawing analogies between these mechanical machines and biological motors is largely inappropriate.

In particular, the effect of length scales should be emphasized when comparing, for instance, a robot in a car manufacturing plant and the biological robot ATPase. While in the first case size, momentum, inertia, and force are important parameters, in the world of molecular machines non-covalent interactions, conformational flexibility, viscosity, and chemical reactivity dominate dynamic function.


(A bird in flight)

A molecular machine, nanite, or nanomachine is a molecular component that produces quasi-mechanical movements (output) in response to specific stimuli (input). In cellular biology, macromolecular machines frequently perform tasks essential for life, such as DNA replication and ATP synthesis. The expression is often more generally applied to molecules that simply mimic functions that occur at the macroscopic level. The term is also common in nanotechnology where a number of highly complex molecular machines have been proposed that are aimed at the goal of constructing a molecular assembler.

Kinesin (A protein-link attached) walking on a microtubule is a molecular biological machine using protein domain dynamics on nanoscales. For the last several decades, chemists and physicists alike have attempted, with varying degrees of success, to miniaturize machines found in the macroscopic world. Molecular machines are at the forefront of cell biology research. The 2016 Nobel Prize in Chemistry was awarded to Jean-Pierre Sauvage, Sir J. Fraser Stoddart, and Bernard L. Feringa for the design and synthesis of molecular machines.

First Generation Light-driven Rotary Motors:

The first light-driven unidirectional rotary motor reported in 1999, has two distinct stereochemical elements: a helical structure (P or M helicity as in the chiroptical switches) and stereocenters (R or S) both in upper and lower halves. The methyl substituents, originally introduced for the purpose of absolute stereochemical determination, can adopt a pseudo-axial or pseudo-equatorial orientation. Photochemical switching experiments revealed a surprising result; helix inversion as detected by CD spectroscopy was commonly associated with trans-cis isomerization in our chiroptical switches but in this case, CD measurements indicated the same helicity for starting material and product. NMR, chiroptical and kinetic studies, supported by calculations, revealed: “the missing isomer” and a sequential process of photoisomerization from stable trans to unstable cis followed by a thermal helix inversion to stable cis. We could show that the photochemically generated unstable cis isomer has the methyl groups in a sterically crowded pseudo-equatorial orientation and by helix inversion restoring the pseudo-axial orientation, strain is relieved. With this serendipitous discovery of a 180-degree unidirectional rotary process, based on energetically uphill photochemical alkene isomerization followed by an energetically downhill thermal helix inversion, we quickly realized that a full unidirectional rotary cycle was within reach by simply repeating the two-step process. The combination of four steps, two ultrafast photochemical steps, each followed by a rate-determining thermal step, add up to a 360-degree unidirectional rotary cycle that can be repeated many times. is system has all characteristics of a power-stroke rotary motor, rotary motion is achieved, fueled by light energy, shows control over directionality, and is a repetitive rotary process. (cis means same sided while trans means opposite sided)

(Structure of A molecular motor)

What Future Holds:

The development of molecular motors arguably offers a fine starting point for the construction of soft robotics, smart materials, and molecular machines. Our ability to design, use and control motor-like functions at the molecular level sets the stage for numerous dynamic molecular systems. Starting with the “synthesis of function”, our focus was to program molecules by incorporating responsive and adaptive properties and being able to control motion. Molecular information systems, responsive materials, smart surfaces and coatings, self-healing materials, delivery systems, precision therapeutics, adaptive catalysts, roving sensors, soft robotics, nanoscale energy converters, and molecular machines are just a small fraction of the systems where fascinating discoveries can be expected and where the ability to control dynamic functions will be essential. As practitioners of the art of building small, we will have to reach out to new levels of sophistication when dealing with complex dynamic molecular systems. In this endeavor, while trying to imagine the unimaginable, Nature’s motors and machines can to some extent guide the molecular explorer. However, at the start of our next journey, we should not forget the words of Leonardo da Vinci:

“Where Nature finishes producing its own species man begins, with the help of Nature, to create an infinity of species.”

About the author: Hassaan Ahmed is a rising junior at LUMS majoring in Physics and Chemistry. Beyond research, he likes to watch current news, all shows of the Paris fashion week, play the violin, listen to classical music, explore food places, and travel.

( Hassaan- A molecular explorer, synthetic materials scientist and, human/hooman)

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