Computational Approaches to Biochemical Reactivity [antikvár]

PREFACE A quantitative description of the action of enzymes and other biological systems is both a challenge and a fundamental requirement for further progress in our understanding of biochemical processes. This can help in practical design of new drugs and in the development of artificial enzymes as well as in fundamental understanding of the factors that control the activity of biological systems. Structural and biochemical studies have yielded major insights about the action of biological molecules and the mechanism of enzymatic reactions. However it is not entirely clear how to use this important information in a consistent and quantitative analysis of the factors that are responsible for rate acceleration in enzyme active sites. The problem is associated with the fact that reaction rates are determined by energetics (i.e. activation energies) and the available experimental methods by themselves cannot provide a correlation between structure and energy. Even mutations of specific active site residues, which are extremely usefiil, cannot tell us about the totality of the interaction between the active site and the substrate. In fact, short of inventing experiments that allow one to measure the forces in enzyme active sites it is hard to see how can one use a direct experimental approach to unambiguously correlate the structure and function of enzymes. In fact, in view of the complexity of biological systems it seems that only computers can handle the task of providing a quantitative structure-function correlation. The use of computer modelling in examining the microscopic nature of enzymatic reactions is relatively young and this book provides a glimpse at the current state of this fast growing field. Although the first hybrid quantum mechanical/molecular mechanical (QM/MM) study of enzymatic reactions was reported two decades ago this is clearly not a mature field and many of the strategies used are not properly developed and no general consensus has been established with regards to the optimal strategy. Moreover, it is clear that many studies are still missing crucial points in their attempt to model biological processes. Many of the problems are due to the complexity of enzyme-substrate systems and the fact that the strategies developed for QM calculations of isolated molecules in the gas phase are not adequate for studies of enzymatic reactions. The same is true for other chemical concepts that should be re-evaluated when applied to complex, non-homogeneous systems. This book presents different approaches that can be useful in theoretical treatments of biological activities. In doing so we try to bring together parts of the overall picture of what is needed in order to model and analyse the energetics and kinetics of enzymatic reactions. As editors, we do not necessarily fully agree with the philosophy of each chapter. However, we believe that presenting different approaches is an optimal way of exposing the reader to the current state of the field and for reaching scientific consensus. Chapter 1 considers the general issue of modelling of chemical vii