Molecular Mechanics and Dynamics Simulations of Enzymes

Abstract

ConclusionsSince the first work describing a molecular dynamics simulation of a small protein was published (McCammon et al. 1977), there has been explosive growth in research concerned with theoretical studies of proteins and enzymes (McCammon and Harvey 1987; Brooks, et al 1988; Warshel 1991). Most of the studies have used empirical energy functions. This chapter describes the nature of the empirical energy function, its use in molecular mechanics calculations and molecular dynamics simulations and presents several applications to enzymes. Most important is the result that starting with x-ray structures of unproductive and static complexes of the enzyme formed with pseudosubstrates and inhibitors, simulations of the enzyme complexed with true substrates can provide direct information on the positions and dynamics of catalytically important residues. This makes it possible to explore the contribution of various amino acids to the enzyme reaction, even without a complete calculation of the reaction path. The latter requires extended potential surfaces of the QM/MM type that include bond rupture and bond formation.Large scale conformational changes play an important role in enzyme function; several examples are reviewed in this chapter. Molecular mechanics calculations, in particular, energy minimization and normal mode calculations, as well as molecular dynamics simulations have been employed to provide an understanding of the mechanisms of such motions and their role in the enzyme.