We have a pupa in a test tube

How did the first computers help break boundaries in chemistry and biology, and which scientists (including Israelis) will receive a Nobel Prize this year for this

The studies and scientists who will receive the Nobel Prize in Chemistry this year

Proteins are probably the most important substances for sustaining life. In addition to the important structural role they play in our body and cells, thousands of tiny protein machines operate in the cells that carry out all the procedures of life: they produce the substances the body needs, break down the food we eat, conduct oxygen to the cells, replicate the DNA, activate the The vaccine and more. Each such protein consists of a very long chain of building blocks - amino acids. The proteins in the living world consist of 20 different such acids, forming a chain of thousands of beads, and sometimes even much more. When the cell finishes producing the long chain, the protein undergoes spatial organization, and receives its three-dimensional, active form. In order for the protein to fold into a stable structure, there must be amino acids in certain areas of the chain that match each other in terms of their chemical properties, electrical charge and physical structure. An error by the cell in the insertion of one or more acids - for example, due to a mutation in the DNA containing the instructions for determining the protein's sequence - may cause the entire protein to be inactive and unable to fulfill its function. Understanding the three-dimensional structure of proteins is extremely important for understanding their activity in the cell. For example, if we want to produce a new drug, we must know what the spatial structure of the protein it is supposed to bind to looks like, so that it is possible to design its molecule in an appropriate way, and ensure effective binding.

Difficult to watch

Determining the spatial structure of a protein is an extremely complex task. The proteins are too small to be observed with a normal microscope, while the use of an electron microscope requires treatment with a material - for example freezing, or a metallic coating - that may change the shape of the protein. An important method that makes it possible to determine the structure of the protein is the creation of a protein crystal, which consists of many identical copies of the same protein. This crystal is irradiated with X-rays, and the scattering of the rays returned from it allows the structure of the protein to be deciphered. However, this method also has notable drawbacks. Many proteins are very difficult to synthesize without destroying them, and the resulting structure is also not always accurate due to tiny changes in the protein structure. It took many years for Ada Yonat (nobel prize winner in chemistry, 2009) to succeed in determining with this method the structure of the ribosome, which consists mostly of protein, precisely due to these limitations. In the 60s, a new player began to enter the arena of biological and chemical research. the computer. Pioneering scientists in their field realized that if they know the properties of certain chemical molecules, advanced computational means will be able to quickly examine their possible combinations, determine which combinations can exist in reality, and also which of the combinations is more likely under certain conditions (eg temperature, acidity, environmental lipids, etc.).

One of the pioneers of the work in the field was Prof. Shinor Lifson from the Weizmann Institute of Science. Lipson, Palma Hanik and one of the founders of Mishmar Ha'emek, developed in his work a formula for calculating the spatial structure of certain molecules, and methods for understanding the thermodynamic behavior of such molecules under different conditions. In the mid-60s, a new research student arrived in Lipson's laboratory - Aryeh Warshel (born 1940), also a kibbutznik (from Sedeh Nahum) who had completed a bachelor's degree at the Technion. Under Lipson's guidance, Werschel began working on developing a computer program that would help determine the structure of molecules. They were later joined by a young researcher who had just completed a PhD in computational biology. Michael (Michael) Levitt was born in South Africa (1947) and did his doctorate at Cambridge University in the UK. He joined the group on a programming expert basis. The computer they had at their disposal was a "Golem" developed at the Weizmann Institute in the early days of computing, and working with it required special expertise (it goes without saying that its computing power was much smaller than the simplest iPhone). The computer programming developed by the three at the Weizmann Institute was a pioneer in the field of the possibility of determining the structure of large biological molecules. The software obviously had many limitations. Among other things, it was possible to determine with it only the structure of a molecule in a state of rest, although many molecules are constantly moving and change their spatial structure accordingly.

See eye to eye

After completing his doctorate at the Weizmann Institute, Warschel went to the USA to work in the laboratory of Prof. Martin Karplus at Harvard University. Karpelos was born in Vienna (1930), and did his doctorate at the California Institute of Technology. As a researcher at Harvard, Karpelos engaged in quantum chemistry - that is, an attempt to understand the part of the smallest components in a chemical reaction. When two molecules react with each other (eg amino acids within a protein), the atoms that make them up attract or repel each other. Those who mediate this reaction are the electrons around the atomic nucleus, and even other elementary particles. In these tiny orders of magnitude, the laws of nature change a little, and the particles obey a different set of laws, which allows them, for example, to transform from matter into energy, or to be in two places at the same time. Varschel and Karpelos harnessed their skills in the fields of computing and quantum chemistry to study retinal, a protein in the retina of the eye, which changes its shape in response to light (as part of the vision process), thanks to the change in the state of the electrons. In 1972, they succeeded in creating a groundbreaking computer program that modeled the activity of this complex protein.

brain drain

Warshel returned to the Weizmann Institute and continued to work with Levitt on developing more sophisticated software. The goal was to understand the structure of enzymes - those sophisticated protein machines that mediate all life processes. The enzymes actually allow a chemical reaction to occur that without them would not have occurred, or would have been very slow, thanks in part to an effect on the quantum environment of the substances involved in it. Understanding the activity of an enzyme requires familiarity with the spatial structure changes in certain regions of it, and with the quantum reactions involved in this. In 1976, Warschel and Levit succeeded in developing the first computer model of an enzymatic reaction. Its importance was not only in the breakthrough, but that this model was suitable for calculating the structures and activities of other giant biological molecules. Later, they included more and more of the software, for example by finding ways to focus on the active regions of the molecule, thus saving calculation operations and optimizing the process. Unfortunately, the work was not completed in Israel. Warshel was not able to get a permanent position at the Weizmann Institute ("He didn't know how to push and market himself because he is not a politician", his wife told Network 2001). They continued the work in Cambridge, and eventually came to California. Warschel accepted a position at the University of Southern California in Los Angeles, and Levitt at Stanford University. However, Levit returned to work for several years at the Weizmann Institute. His family lives most of the time in Rehovot, and he frequently stays at the institute as a visiting professor. The founder of the field, Lipson, passed away in XNUMX, and did not get to be a partner in the prestigious award.

Foundations for the future

The breakthroughs led by Lipson, Warshel, Levitt and Karpelos, along with the meteoric progress of the computing world, resulted in the fact that today powerful tools are at the disposal of chemists and biologists seeking to decipher the structure of various substances, predict chemical reactions in advance or develop new materials. Computational chemistry, structural biology and bioinformatics are fields of research that largely stand on the foundations laid by these researchers. These tools are used in drug development, in industry as well as in pure research, and make it possible, for example, to produce more effective drugs, to determine the sequence of genes, to refine chemical reactions to reduce production processes, and to develop more environmentally friendly processes. In the coming years, this field is expected to continue to progress. Today, scientists are working on computer models that will simulate a significant part of the brain's activity, for example, and perhaps one day it will be possible to establish computer models of whole creatures on these bases as well - something that will surely catapult medicine into a new and fascinating era.