Enzyme dynamics and catalysis in the mechanism of DNA polymerase
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Enzyme dynamics and catalysis in the mechanism of DNA polymerase Adrian J. Mulholland • Adrian E. Roitberg In˜aki Tun˜o´n
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Received: 24 September 2012 / Accepted: 26 September 2012 / Published online: 23 November 2012 Ó Springer-Verlag Berlin Heidelberg 2012
Abstract This contribution contains the commentaries of the three authors about two papers in this issue of TCA that present alternative views of the role of conformational changes in the specificity of enzyme DNA polymerase b. Concepts such as dynamical effects, the induced fit model or the importance of sampling in modeling of enzymatic reactions are briefly revised within the context of the debate established in the two previous papers. Keywords Enzyme dynamics Enzymatic catalysis Dynamical effects DNA polymerase
Editor’s Note: This paper and papers by Schlick T, Arora K, Beard WA, Wilson SH (doi:10.1007/s00214-012-1287-7) and Ram Prasad B, Kamerlin SCL, Floria´n J, Warshel A (doi:10.1007/s00214-012-1288-6) document and discuss contrasting outlooks on the questions of prechemistry and catalysis in DNA polymerase. All authors were initially provided with one another’s manuscripts, at which point opportunities to make revisions were offered, and finally Mulholland, Roitberg, and Tun˜o´n were given the ’last word’ on the revised manuscripts in their role as commentators. The editors of TCA hope that this discussion will illuminate key issues affecting ongoing work in this area. A. J. Mulholland (&) Centre for Computational Chemistry, School of Chemistry, University of Bristol, Bristol BS8 1TS, UK e-mail: [email protected] A. E. Roitberg (&) Department of Chemistry and Quantum Theory Project, University of Florida, Gainesville, FL 32611-8435, USA e-mail: [email protected] I. Tun˜o´n (&) Departamento de Quı´mica Fı´sica, Universidad de Valencia, 46100 Burjasot, Spain e-mail: [email protected]
Few topics in current research in chemical biology provoke as much passionate debate and heated arguments as the question of the role of dynamics in enzyme activity. The fascinating catalytic power of enzymes has led many to hypothesize over the years about exactly what factors have been optimized by evolution to make them such good catalysts. Detailed understanding of how enzymes ‘‘work’’ should help in the development of efficient, ‘‘green’’ catalysts for practical applications as well as inhibitor design against various diseases. This puts the issue in a wider focus of important practical applications. While there has been encouraging progress in designing and evolving enzyme-like catalysts, they are generally considerably less efficient, leading some to claim that we lack enough understanding of the principles that underlie enzyme catalysis. Many ideas put forward to explain this lack of understanding focus on enzyme dynamics, and propose that complex protein motions are at the heart of catalysis [1]. For example, it is widely suggested that enzymes have evolved to modulate quantum tunneling by their motions [2]. Some researche
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