Computer Simulation and Analysis of the Reaction Pathway of Triosephosphate Isomerase

P. A. Bash, M. J. Field, R. C. Davenport, G. A. Petsko, D. Ringe, and M. Karplus Biochemistry 1991, 30, 5826

Contributed by +Jan Jensen 

In honor of the 2013 Nobel Prize in Chemistry I am highlighting this gem from 22 years ago by Karplus and co-workers.  I believe (correct me if I'm wrong) that this paper presents the first study of enzyme catalysis using "conventional" QM/MM: conventional electronic structure theory (AM1) combined with a standard protein force field (CHARMM).    

When the paper came out I had recently started as a PhD student and one of my projects was working on the Effective Fragment Potential QM/MM method.  At that time it was relatively easy to keep track of the QM/MM literature and two papers were usually on top of my rather short stack of QM/MM papers: Singh & Kollman and Field, Bash & Karplus.  As I remember it, I was reading them during an extended visit to the Center for Advanced Research in Biotechnology in Maryland and sitting there it was pretty hard to imagine, based on the applications in these papers, how QM/MM would ever help advance research in biotechnology.  There was a hint in the Field, Bash, and Karplus paper, where they used something called Triose Phosphate Isomerase (TIM) to motivate the use of link atoms, but it wasn't until the Biochemistry paper that all the pieces were put together.  

All of a sudden (semi-empirical) electronic structure theory could be used to say something meaningful about a system with a thousand atoms (1650 to be exact).  Specifically that Lys12 is most important to catalysis and His95 could act as an acid/base catalyst.

Despite being the first of its kind, the paper still reads very much like a "modern" study and I think it is fair to say that most subsequent QM/MM studies of enzymes are really variations on the themes introduced in this paper.

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