From bull horns to under the lens of Anton

In 1988, a young computer scientist named David Shaw was working at Morgan Stanley, one of the first Wall Street firms interested in using computer algorithms for trading. Shaw was an expert in parallel processing, speeding up calculations by executing them in a parallel process over multiple processors. Previously he had been a computer science professor at Columbia University had tried to sell his computer skills to a number of companies, but only Morgan Stanley was genuinely interested. As Shaw started working at the company, he began to think not just of programming strategies but of creative ways in which they could be applied to trading. In a meeting where he was supposed to talk only about his algorithms, he went one step beyond and described better methods for trading using these algorithms. Eyebrows went up in the room. Shaw was essentially seen as overstepping his bounds as a programmer. The higher-ups told him clearly that his job was simply building the computer architecture. He could leave the trading to them. Shaw quit and started his own company. Ten years later, it was one of the most successful hedge funds in the world and Shaw was a billionaire. One can only speculative how much the Morgan Stanley executives cried over the loss they had suffered when Shaw left.

But now D E Shaw is a totally different animal.

One of the most anticipated talks at the American Chemical Society meeting in Boston which I just came back from was by this Wall Street mover turned pure scientist. He is a remarkable and brilliant man. What other Wall Street hedge fund manager who made billions using mathematical algorithms for trading (and was known as “King Quant” at one point) basically retires from the dizzying world of finance to fully engage himself with computer simulations of proteins and drug discovery research? Well, Shaw has done this, and is blazing his way toward some potentially revolutionary research. In a nutshell, molecular dynamics (MD) is a technique that simulates the motions of systems at the molecular and atomic levels. It is especially useful for proteins since it can accurately capture their real-life motion in living organisms. MD is based on Newton's laws of motions and essentially involves solving the equations of motions to calculate the forces and velocities of all the atoms in the system. In practice, due to the very large number of atoms in a typical protein (usually thousands, surrounded by tens of thousands of water molecules) MD is quite computationally intensive and challenging to implement; until now, most simulations have been restricted to nanosecond time frames (which can easily correspond to days of actual computer time).

Shaw heads D E Shaw Research, a company totally separate from the financial powerhouse that has as its long-term goal, a fundamental transformation in the process of drug discovery. As the story goes, Shaw got somewhat bored of making millions and wanted to attack scientific problems that could benefit from the application of advanced computer algorithms. He got his old job as computer science professor at Columbia University and started looking around for the right problem. Fortunately for the field of biochemistry, Shaw started having discussions with a friend of his, the well-known physical chemist Richard Friesner at Columbia who is also the chief scientific advisor for the computational chemistry company Schrodinger. Friesner piqued Shaw’s interest and started giving him little problems in computational chemistry and biology which Shaw solved during his spare time. Finally he realized that MD simulations of proteins which had previously been typically restricted to the nanosecond time range stood a chance of being truly and very significantly useful if they could be expanded to the 10 microsecond-millisecond range, since this is the time scale on which most interesting biological motions occur.

Shaw started D E Shaw research and collected a team of highly talented chemists, biologists and computer scientists to tackle the problem. After a decade or so, these efforts have manifested themselves as Desmond, a protein MD program that has vastly accelerated computer simulations of proteins. Desmond essentially relies on many ingenious methods to simplify the calculation of forces and velocities involved in a typical MD computation. What is even more remarkable is that Shaw’s group has designed ‘Anton’, a 512 node state-of-the-art machine, a special purpose machine explicitly designed for protein MD and named after Anton van Leeuwenhoek, the legendary 17th century Dutch scientist who trained the microscope on the microbial world and unearthed a wondrous universe teeming with life. Just like the 17th century Anton probed the events of the bacterial world, the 21st century Anton seeks to probe the molecular-level events of the protein world, The machine does only MD, and it does this using a razor sharp scalpel.

To give an idea of the kind of quantum leap Anton provides for MD simulations, Shaw gave some numbers, and I can swear I saw some people who were almost nodding off suddenly become wide awake. According to Shaw, the fastest supercomputer which does parallel processing today can crunch about 200 nanoseconds per day for a typical sized protein. Anton surpasses this number by two orders of magnitudes and spews out 17,400 ns or 17 microseconds per day. Such numbers would have been unthinkable a decade ago; until Desmond appeared on the scene, the world record for long protein MD simulations had been held by a group from the University of Illinois, with a total time of 10 microseconds.

So what’s the significance of being able to simulate in this time scale? Tremendous. It’s like the difference between nuclear weapons and the biggest conventional bombs previously available. When nukes arrived on the scene, some politicians like Winston Churchill shrugged them off by thinking that they were “just bigger bombs”. But as the old saying goes, quantity can have a quality all of its own. Nuclear weapons heralded a completely new era of warfare because of the ability of a single weapon to raze a whole city. The basic unit of destruction changed from a human being to entire cities. Desmond and Anton promise such conceptual transformations. As mentioned before, breaking the 10 microsecond barrier is a real turning point since most interesting physiological events happen on time scales of microseconds-milliseconds.

Entering the world of millisecond simulations is like unlocking the door to a rainforest with millions of exotic species that you suspected existed, but which you had no way of viewing and studying. In the last few years, Desmond has been used to study highly significant conduction events in ion channels proteins which conduct sodium and potassium, has been used to reconcile experimental and conceptual contradictions in the structure of proteins called G-Protein Coupled Receptors which are absolutely crucial in both basic physiological processes and in the action of drugs, and has been used to study proteins called kinases whose misregulation in involved in cancer. All these events are very slow with respect to conventional MD and were until now mostly inaccessible. Shaw showed some spectacular examples of proteins actually folding and unfolding multiple times. In some cases his group has obtained quantitative agreement with experiments.

I think it was the end of the talk which made a few jaws drop. When you have a protein structure and want to find out a small drug molecule which can modulate its activity, one of the key goals is to first find out where the drug binds. Almost all drugs regulate the activity of proteins- and therefore treat diseases in which these proteins are misregulated- by binding into very specific pockets on the proteins. With the kinds of time scales available, Shaw can achieve this with a devastatingly straightforward simulation. In a video that appeared a little surreal, he simply let the drug roam all around the protein surface and find the binding pocket. Like a curious dog sniffing around for the buried bone, the little guy went in and out of crevices and gullies, lingered for some time outside the binding site, and then, with a little hesitation, finally ensconced himself firmly in his cozy home.

Molecular dynamics by itself is not going to revolutionize drug discovery. But it can provide unprecedented insight into the behavior of biological systems at the molecular level. What we witnessed in that room on Thursday was a different ball game. One in which the ball had been hit out of the park. More surprises should follow.