Computational Enzymology

University Of California-Santa Barbara, Santa Barbara CA

Investigators

Abstract

Catalysis and design of catalysts is presently deemed to be of great practical importance. Natural enzymes are the most proficient catalysts that we are aware of. Some fifty years of research in the field of structural biochemistry has provided detailed structures of many enzymes by x-ray crystallography. Even X-ray structures of high resolution suffer in that they are only averages of many dynamic structures and structures present in less than 25% of the time are not included in the averaged structure. Molecular dynamic simulations (MDS) provide individual conformers and those present less than 25% of the time can be isolated. The general question of why enzymatic reactions are so efficient has been, in the mind of many, answered by the Pauling tenet that the transition state (TS) is bound to the enzyme in preference to the ground state substrates (S) thus stabilizing the TS. Using X-ray coordinates of enzyme species, secondary kinetic isotope effects and other means one can derive the structures of the enzyme bound S (E*S) and transition state (E*TS) and by MDS observe these structures and their dynamic motions. By this means one can determine if E*TS is an appropriately tighter complex than is E*S. Is the Pauling tenet a useful proposal? Does the emerging concept of the importance of correlative motions in E*TS formation have value? This will be determined by examining the E*S and E*TS structures for a number of enzymes (diphtheria toxin NAD+ hydrolase, C. fasciculata nucleoside hydrolase, formate dehydogenase, liver alcohol dehydrogenase).