How do enzymes really work?

My understanding is that “reflections” can cover a multitude of sins. I have previously written a brief history of my career, and do not want to duplicate that exposition (1). Instead, this “reflection” will trace a primary focus of my laboratory for many decades, namely how do enzymes achieve their remarkable catalytic efficiency? (Indeed this has been a focal point of the field of biochemistry for a much longer period.) This discussion will include personal interjections that trace my progress from undergraduate years to the present, as well as describing some of the other areas pursued in my research program. The answer to the question posed in molecular terms has been elusive, even though it has been a central theme of many research programs, including my own. A complete review of this subject is far beyond the scope of this article. Instead I will review this subject as reflected in my personal interests and research program, although some historical perspective is included. I apologize in advance for not including all of the many noteworthy people and references that have significantly advanced the understanding of enzyme catalysis. My entry into the field of enzymology as an independent investigator occurred in 1960 when I was hired as an Instructor at MIT. My background included a graduate degree in Physical Chemistry from the University of Wisconsin where I did my graduate work in the laboratory of Robert Alberty, a wonderful mentor as well as a leading figure in the field of steady state enzyme kinetics. This was followed by a postdoctoral year in the laboratory of Manfred Eigen in Gottingen who developed the field of relaxation methods and received the Nobel Prize in 1967. These methods revolutionized the field of solution kinetics, and I was very fortunate to have the opportunity of working closely with him.