A fraction of a second after the Big Bang, the universe consisted only of divided matter – in other words, elementary particles – combined with light and energy. As things cooled down, condensed matter made its first appearance. Particles combined to make atoms, and atoms combined to make molecules.
Eventually, molecules began to organise based on physical and chemical principles into increasingly complex configurations, eventually making the crucial transition from non-living matter to the first life forms. The history of our universe – and ourselves – makes it clear that the chemistry of molecules is vital to the inner workings of everything around us.
On Monday, two Nobel Laureates in Chemistry spoke about significant progress made throughout the last four decades by researchers in the field of molecular chemistry. Jean-Marie Lehn and Arieh Warshel both gave their Agora Talks on the second day of the 70th Lindau Nobel Laureate Meeting. Lehn discussed the importance of molecular interactions to the life sciences, while Warshel summarised new approaches to studying complex molecular dynamics.
Supramolecular Chemistry and Beyond
Lehn began his Agora Talk with a brief overview of two major milestones in molecular chemistry. The first occurred in 1828 – which he acknowledges as the beginning of the field as a whole – when Friedrich Wöhler carried out several reactions that resulted in the synthesis of urea. This discovery represents the first production in the laboratory of an organic substance without the intervention of living matter.
The second milestone was achieved through the collaborative efforts of Robert Burns Woodward and Albert Eschenmoser almost 150 years later. Together, their groups successfully accomplished total synthesis of the biomolecule vitamin B12. It is the most complex of all known vitamins, and the project required the labor of no less than 91 postdoctoral researchers and 12 graduate students over a period of almost 12 years.
“Molecular chemistry is the art and science of the organization of molecular matter by handling the bricks of matter – the atoms, the elements,” said Lehn, who received the 1987 Nobel Prize in Chemistry for the development and use of molecules with structure-specific interactions of high selectivity. “[Vitamin B12 synthesis occurred] already 50 years ago, and now molecular chemistry has evolved much further.”
Today, molecular chemistry is a well-established field that has invented new types of reactions, processes, materials, molecules, and drugs. His recent research interests lie in a sub-field known as supramolecular chemistry, which focuses on molecular assemblies and the intramolecular bond.
“Supramolecular chemistry is a chemistry beyond the molecule,” he said. “It is based on what happens with compilations of molecules go together, interact with each other, recognize one another, and so on.”
Lehn has long believed that, in the same way that covalent bonds between atoms have been studied and manipulated for decades, chemists should tackle noncovalent intramolecular forces with the same vigor.
Indeed, supramolecular chemistry has grown exponentially in the last few decades, with studies falling into three main categories: molecular recognition, supramolecular reactivity, and membrane transport processes. Molecular recognition examines how molecules recognize one another when in proximity, such as how natural killer cells know to attack cancer cells. Supramolecular reactivity looks at what happens when molecules attach to one another. And studies on membrane transport processes investigate how molecules pass through membranes to get inside a cell.
The study of molecular interactions and bonds also has a number of life science applications such as drug discovery, optical labels for medical diagnostics, gene transfer, and supramolecular biomaterials.
“Molecular recognition is the way to drug discovery,” said Lehn. “A drug is a molecular key for a biological lock, and the best fitting key is the best drug.”
New Models to Understand Molecular Dynamics
For his Agora Talk, Warshel highlighted achievements in the field of molecular dynamics, which uses computer simulation methods to analyze the physical movements of atoms and molecules.
“Molecular dynamics is basically solving Newton’s equations of motion. In some simple cases, there is an analytical solution. For a single body and central force, it works very well,” said Warshel, who received the 2013 Nobel Prize in Chemistry for the development of multiscale models for complex chemical systems. “For more complex cases with many bodies, you have to use a computer.”
Simulation studies are often constrained by the amount of computational power available. For instance, simulation size, integration timestep, and total time duration can all be varied to design a more practical simulation that will finish within a reasonable time period. But the simulations also need to be long enough to encompass the natural processes being studied.
„For molecules with many atoms, a typical timestep is a femtosecond, so you need a lot of computer power to move to relevant times,” he said. “In the mid-1970s, you could not really model anything which would be more than one or two picoseconds.”
The first molecular dynamics simulation of a biological process was published by Warshel and his colleagues in 1976, with the primary process taking about 100 femtoseconds. Everything was predicted correctly, according to Warshel, because the computer time available matched the question at hand.
Processes like protein motion that take longer than a few picoseconds could not be simulated reliably back then because of computational constraints. Today, computers are much more powerful, but it is still difficult and time-consuming to model many biological processes with large molecules by direct dynamics.
Innovative approaches that get around this issue, such as modeling Brownian motion and using time-dependent Monte Carlo methods, are new ways of working smarter and not just harder. Trajectories and interactions between key biomolecules are calculated using Brownian dynamics methods, while other components of the system, instead of being explicitly included in the simulation, contribute collectively as a random force. Warshel gave the example of modeling proton transport in biology, which is cumbersome with direct dynamics, but becomes a much simpler problem using Brownian dynamics methods.