Molecular dynamics simulation of enzymes

Wang S, Hu P, Zhang Y (2007) Ab initio quantum mechanical/molecular mechanical molecular dynamics simulation of enzyme catalysis the case of histone lysine methyltransferase set7/9. J Phys Chem B ASAP... 

Molecular dynamics simulations of enzyme reactions have been performed successfully with semiempirical QM/MM methods [54,57,64,72] (see section 6). The sampling provided by such QM/MM molecular dynamics simulations may be used to calculate activation free energies (and to address dynamical effects on the reaction). Thus, semiempirical QM/MM simulations have an important role to play. It has been suggested that a mapping procedure can be used to calculate ab initio QM/MM reaction free energies from empirical valence bond simulations [39,176]. This approach shows promise, but calculation of energies within the QM system (as opposed to its interaction with its surroundings) from such a simulation remains problematic. 

Fig. 7.15 The variation in torsion angles can be effectively represented as a series of dials, where the time corresponds to the distance from the centre of the dial. Data from a molecular dynamics simulation of an intermolecular complex between the enzyme dihydrofolate reductase and a triazine inhibitor [Leach and Klein 1995].

Tapia and Eklund (1986) carried out a Monte Carlo simulation of the substrate channel of liver alcohol dehydrogenase, based on the X-ray diffraction structure for this enzyme. The addition of substrate and the associated conformation change induce an order—disorder transition for the solvent in the channel. A solvent network, connecting the active-site zinc ion and the protein surface, may provide the basis for a proton relay system. A molecular dynamics simulation of carbonic anhydrase showed two proton relay networks connecting the active-site zinc atom to the surrounding solvent (Vedani et ai, 1989). They remain intact when the substrate, HCOf, is bound. 

We report the results from a molecular dynamics simulation of the serine protease y-chymotrypsin (y-CT) in hexane. The active site of chymotrypsin contains the "catalytic triad" which consists of Ser-His-Asp. y-CT suspended in nearly anhydrous solvents has been found to be catalytically active. In order for proteins to retain their activity in anhydrous solvents some water molecules are required to be present. These "essential waters" have been suggested to function as a molecular lubricant for the protein. Hexane, having a dielectric constant of 1.89, is a suitable non-aqueous solvent for enzymatic reactions. The low dielectric constant of hexane allows it to not compete with the protein for the essential water and allows enzymes to retain their catalytic activity. y-CT in hexane is thus an ideal system to further explore the effect of non-aqueous solvation on protein structure, function and dynamics. 

The enzyme mechanism of NA of influenza virus has been investigated by kinetic isotope methods, NMR, and a molecular dynamics simulation of the enzyme-substrate complex. 

Recently, molecular dynamics simulations of carboxypeptidase A have been employed to further our understanding of the enzymatic mechanism of carboxypeptidase A (Makinen et al. 1989 Banci et al. 1992 Banci et al. 1993 Stote and Karplus 1995). In an early study, molecular dynamics simulations were used to characterize the secondary structure motion of enzyme as well as the motion of the different subsites... 

Since 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... 

Billeter, S.R., et al. (2001). Hybrid approach for including electronic and nuclear quantum effects in molecular dynamics simulations of hydrogen transfer reactions in enzymes. J. Chem. Phys. 114, 6925-6936... 

Recently, semiempirical molecular-orbital methods have been combined with force-field-based molecular-dynamics techniques into hybrid schemes The interesting part of the system is described by quantum chemistry, while the surroundings are treated by a classical force field. These hybrid schemes allow calculation of the energy and gradients fast enough for molecular dynamics simulations of hundreds of picoseconds (10s time steps) duration to be feasible. This provides sufficient sampling for the calculation of many statistical-mechanical properties. A short synopsis is given of work carried out at ETH Zurich on conformational equilibria in solution, reactions in solution and enzyme reactions. 

An important question regarding peptides and proteins is concerned with the equilibria among several conformational states. It has been suggested that enzyme function may be linked to the occurrence of particular conformations in solution.24 377 A mechanism recently proposed for the hydrolysis of oligosa-charides by the enzyme lysozyme, for example, is based on the observation of specific substrate and enzyme sidechain conformations in a molecular dynamics simulation of a lysozyme-substrate complex.378 Also, local conformational equilibria and the barriers between conformations are important in determining the rates and mechanisms of folding and rebinding processes. 

A. D. MacKerell, Jr., L. Nilsson, R. Rigler, and W. Saenger, Biochemistry, 27,4547 (1988). Molecular Dynamics Simulations of Ribonuclease Tl Analysis of the Effect of Solvent on the Structure, Fluctuations, and Active Site of the Free Enzyme. 

The role of protein motions in dihydrofolate reductase (DHFR) has been examined using molecular dynamics simulations as well as experimental studies of mutant enzymes. DHFR catalyzes transfer of hydride from NADPH to dihydrofolate via a tunneling mechanism. Molecular dynamics simulations of complexes of the enzyme with both substrates show both correlated and anticorrelated motions (see Figure 23). " Mutations... 

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