Systematic procedure for the development of accurate QM/MM model Hamiltonians

Abstract

Enzymes play a crucial role in the biochemical machinery, serving as extraordinarily specific, highly efficient and regulatable catalysts of the fundamental chemical reactions that occur in living organisms. Understanding the mechanisms by which enzymes achieve their remarkable catalytic abilities has been a long-standing goal of biochemists, and significant progress has been made since 1878 when Fredrich Wilhelm Kühne first coined the word ‘enzyme’ (from the Greek en in + zyme leaven) to emphasize that there was some agent in yeast cells and not the yeast itself that was responsible for fermentation. Biochemists have since deduced that enzymes are proteins, composed of sequences of amino acids, and have developed powerful experimental techniques for determining the precise amino acid sequences that define proteins. Moreover, it is possible to modify individual residues through site-directed mutagenesis techniques to help identify the key functional groups of the enzyme. Additionally, X-ray crystallography has advanced to the point where it is now feasible to determine the three-dimensional structure of enzymes, providing us with the ability to visualize the active site and confirm Emil Fischer’s 1894 hypothesis that the specificity of an enzyme for a particular substrate is due to their geometrically complementary structures.