The connection between quantum physics and organic chemistry. Part two of the interview given by Nobel laureate Prof. Aryeh Warshel to the Hidan website

Prof. Aryeh Warshel: "The first article that combines quantum physics and classical physics as applied to chemistry was actually a work I did at the Weizmann Institute while waiting for a post."

In the first part of the series of articles based on an interview we conducted with Prof. Aryeh Warshel He describes the speed with which he finished his master's degree and doctorate at the Weizmann Institute, thanks to his development of simplifying the complicated formulas to a single line of code on the computer. He was of course asked to do a post-doctorate abroad like every PhD graduate, but he had a lot of free time in between.

"In order to fill the free time on the way to the post, I did a few jobs on the side and one of them was the basis for what we received the Nobel Prize for - a combination of quantum and classical. I had a friend at the Biological Institute in Nes Ziona, his name was Avraham Bromberg. He worked in chemistry and measured the isotope effect of a molecule with three rings that reacts with oxygen. When he tried to present it at conferences at the Institute, the experts in the field said that there could not be such a large tunneling effect that causes such a quick reaction. We decided that I would write a program that would calculate the effect of quantum tunneling - the passage through the barrier to test how important it is. So I already had the program that could calculate the vibrations of a molecule, but the reaction with the oxygen had to be calculated according to the laws of quantum mechanics. I took a chemistry book and programmed the description of the quantum part using the valance bond theory method (the method of describing quantum behavior that Linus Pauling promoted) but programming using the valence bond theory method is complicated because it requires very complicated formulas, which are different for each reaction and most of the computer work in quantum chemistry has become much easier More programming using the molecular orbitals method that was later used in many of my studies. I was able to program the complicated expression describing the quantum part and get the huge effect that Bromberg measured."

"It was actually the first paper that connects quantum theory and classical mechanics. Then Karpelos came to the Institute for a half-sabbatical and I went to him for a post doc and we decided that it might be worth using the Molecular Orbitals method to calculate the behavior of the retinal molecule, a small molecule that binds to a protein in the retina of the eye, which changes its shape in response to light (as part of the vision process). Among the important things I came up with during my stay at the post in Boston was to put together the program from the institute (called Consistent Force Filed, where Lipson invented it, or in Hebrew, a coordinated field). The idea was to connect the software with calculations of π electrons - a method where you look at molecules like benzene and describe only the electrons that are non-localized in a quantum way, so you get a good description of their spectrum. There have always been articles that said you can get a good approximation of the spectrum but not the structure of the spectrum and vibrations together. Where I came from there was no such thing as impossible. By improving the parameters in the model we were able to obtain a description of the molecule and all its properties: electronic transitions, vibrations, energy and structure. I used the same method to improve the parameters in the classical software to the one in which there was a quantum mechanical description for the conjugated electrons."

"Anecdote about this - the software I wrote was for 30-40 years the best means of studying molecules that are conjugated including molecules that have color inside proteins and many in the quantum community who liked quantum models in which all electrons are taken into account, including those in atoms that are not involved in the π bond got the This (although many experimenters used the software). When they discovered Buckyballs, for which they received a Nobel Prize, theorists tried to calculate the oscillations of Buckyballs using Hard Core Quantum Mechanics methods, and half of the article was devoted to the fact that they got better results in my program, but it must be a coincidence. But that was all because I insisted on matching the parameters to my experiments and since the physics of the model were good then it worked well. "

"In this program, which I called QCFF/PI, I used it to look, for example, at the photochemistry of rhodopsin, the pigment molecule in the eye. In an article I published in Nature in 1976 I presented the first work of Molecular Dynamics in biology, when I took the molecule, put it in an excited state and did a simulation where I showed how it rotates and changes from the cis isomer to the trans isomer. (See an explanation on Wikipedia). In the first stage of the proof, the molecule sits inside the protein in a cis structure and moves to the opposite structure - trans. So the process was thought to take more than 6 picoseconds. In this calculation I found it to be 100 femtoseconds. I calculated exactly what they found years later experimentally. No one believed - there were people who wrote whole articles trying to prove that it couldn't be."

"This is also a good example of the way I work. At the same time people were talking about photochemistry, they were talking about energy levels that have many vibrational levels and you put light into them and then a process known as Radiationless Transition takes place from which you can tell how a molecule in the excited state goes from cis to trans. Back in 1971, I read an article where people worked on small molecules and instead of looking at a contour of vibrations, they saw what the chances of transitioning between the different states are - a semi-classical model. I suddenly realized that this is the method that can be used in any photochemical process."

"The understanding that this method they did for H + HH reactions is the correct method to use for large molecules. And after that I used this method to be the first to discover what really happens in the first step of the photosynthesis process. It took a while for people to understand that this is how it should be looked at. (Refer to the movies on the website). Everything I predicted in 1976 turned out to be true down to the last detail numerically and in recent years also computationally.

"But let's go back a moment, to the time when I returned from the post and just wanted to perform a quantum mechanics calculation for each organic molecule. I wrote a complicated and beautiful software that until today no one but me has used, and the intention was that one day I would work on enzymes. At that time Levitt returned to the institute and we started working on protein folding. He developed the CFF software to the point where it can be used to describe any type of protein or large molecule. For this program it did not matter what the size of the molecule was. He then worked on the enzyme lysozyme and showed that lysozyme works by the fact that the forces of the proteins take the sugar and move it from a chair shape to a sofa shape. The sofa is more similar to the shape that sugar has in the transition state where the bond is broken (STRAIN HYPOTHESIS). Mike showed that tension cannot be used to explain catalysis (something that seems obvious to me but was a breakthrough). I decided not to see what doesn't work but what does work and for that I had to do the chemistry and break the bond with lyses. At that time, because the work on folding with Mike made a big impact, I received an EMBO scholarship and joined him to work at the Center for Medical Research in Cambridge. And I was attracted to my things - working on hemoglobin and other things and trying to decipher the behavior of enzymes. When I tried in my program to break the bond in lysozymes the disintegration happens several billion times faster than in solution. I connected my program that already knew how to handle quantum mechanics with Mike's program and tried to break the connection and it didn't work. It turned out that doing chemistry in protein is 50 kilocalories higher than doing it in water, which of course is not true. The answer was that what I was doing was wrong, that it was impossible for me to get an enzyme that worked 10 times slower than Bam. something is missing. And what I realized was missing is that when you break a bond of carbon and oxygen in a gas (without water, without an enzyme), the bond breaks into radicals (an electron on the carbon and an electron on the oxygen) and it always costs 80 kilocalories. It is impossible to do it faster, but in water the bond is broken into carbon plus and oxygen minus and the reason this happens is that the water or the protein stabilizes in its electrostatic field near the minus positive effects from the environment and near the plus there are effects of negative charges."

Chemists got unrealistic results when they tried to model the reaction H2O+H2O OH- +H3O+ and simply used quantum mechanics without the effect of water and therefore got wrong results. I insisted on solving the relevant question. When I saw the problem I went to the library, wasted a few months and saw that no chemist tried to solve the problems what the water or protein effect is missing in the quantum part of the program. These are three lines of computer code if you know where to put them.

"To recognize the quantum effect, you only need to add one letter in the formula. Until 1973 all attempts to do this involved observing the interaction of all the molecules and their environment in an approach that had no chance of working in any way in reality. My approach was, as mentioned, that one should look at the first formula in the book and not continue reading. I already saw in the first formula that there are charges of quantum atoms that enter the region of other quantum atoms, understanding from this what is the effect of charges of atom A on atom B. Everything I did - a completely general formula instead of atom A being quantum we will put the charge from atom A which is classical. It was the first real QMMM software that led to all the breakthroughs in the field. If the charges of the classical environment were to be added to the quantum mechanics, a description of water around the protein would be needed. At the time, people didn't know how to do it and it was clear that it couldn't be done. We built a grid of cubes that each have a dipole instead of water and we taught these dipoles to turn towards the charges and we also trained them to give the same contribution as water."

"In the article from 76, which is the center of the Nobel, we also solved the problem of the treatment of electrostatic energies in proteins. Instead of thinking that it can't be done and it never will be possible to do it and maybe we should use Maxwell's laws for electrostatics I didn't believe in any formula. My approach, that everything should be represented in a molecular way - it doesn't matter if in a completely simple way, is contrary to the approach that existed in theoretical chemistry that you need to represent everything as accurately as possible."

In all the years after that, I mostly tried to explain how enzymes work and I'm sure that my programs explain it completely, but there were also great difficulties in this because the last thing people want is for other people to explain to them how such a puzzle works. And all this is done with the help of the electrostatic part added in 76.

"Today the whole community uses these methods. But even on this there were those who asked how it is possible that such a childish method gives correct results, this is a method that allowed me to explain in a quantitative way how they work and more importantly how they don't work, and part of these years was to turn these methods into quantitative methods and how much time to waste energy and explain to them that even though it seems like I dreamed about it in the middle of the night it's also mine. They never read my complicated articles. "

"Rudy Marcus, who received a Nobel Prize for Electron Transfer, and whose 90th birthday we recently celebrated, used to tell me that there are two Arya and Rachel, and it is impossible for the same person to write both types of articles. The articles in which I developed the method people decided should not be read and articles in which I used intuition decided that it could not be true. Fortunately, a computer program is something that speaks for itself.

After a long conversation that discussed the scientific part and which you could read in the first part and the second part of the series, I asked for Prof. Warshel's reference to the issue that was raised in the media on the day the award was announced, regarding the non-granting of tenure by the Weizmann Institute.

Why didn't you actually stay at the Weizmann Institute?
I completed the post at Harvard until 1972. Immediately after that, I returned to the institute and, as mentioned, continued research with Levitt. At one point they didn't give me tenure because they decided it wasn't possible for me to be doing what I was doing. that is not possible. They chose to listen to slander. After that they gave me the position of a professor without tenure, I went to Southern California to wait to see what they would decide at the institute. After the decision not to give me tenure I decided to stay in California and have been there ever since.

Surely you are aware that similar stings were done to Ada Yonat as well? (Actually she was fired but somehow managed to be saved, see An interview I had with her in 2009. father.)
"The difference is that Ada Yonat was there two years ago, so they made fewer tricks. They gave her a small room as a laboratory, but they also gave her tenure. In one of the institute's responses, they claimed that if I had patience they would have given me tenure. I twice submitted a request to them to change the decision, and I even had good recommendations in the form of Prof. Lipson and letters from Nobel Prize winners, it didn't take much effort to believe the slanderers. For those who do not understand what the computer can do, it would be very easy to believe that it is not possible. Prof. Elisha Hess from Bar Ilan summarized my case and said that it is not the brain drain but the smuggling of the brains."

"On the other hand, when I was asked if you have limited resources, you have to make difficult decisions. Today I read about the brain drain from Poland in the journal of the Royal Society of Chemistry. When you have limited resources it happens and there is an objective difficulty that you cannot find out what the next thing will be. Once when we were discussing my tenure at USC, one of the recommenders said that there are two models in science - one is a very good professor who did what others do better than them and there is my model that makes everything different and he said that my model leads to geniuses and the other model does not. It was in '81. There is a difficulty, but what is important is that if there are negative letters to someone who does original things, this is where the Israelis are very good at using the bad qualities they have - looking for flaws. Not that they don't do it in America, but the Israelis are a little better at it."
Thanks to Dr. Moshe Nachmani for his help in clarifying the technical terms in chemistry.

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