Molecular dynamics simulations of a protein-protein dimer: Particle-mesh Ewald electrostatic model yields far superior results to standard cutoff model

In this article we present two 1000 ps molecular dynamics simulations on th e rat mu-glutathione S-transferase dimeric enzyme in complex with the produ ct 1-(S-glutathionyl)-2,4-dinitrobenzene, in a periodic box with explicit s olvent molecules, and investigate the effect of long-range electrostatics m odels on the structure and dynamics of the dimer and its components. One si mulation used the standard cutoff method 10 Angstrom, whilst the other used the particle-mesh Ewald (PME) method. We monitored the root mean-square at omic deviation (RMSD) from the initial crystal structure to examine the con vergence of both simulations, as well as several other structural parameter s such as the distance between active sites, rigid body rotation between do mains in subunits, radius of gyration, B-factors, number of hydrogen bonds and salt bridges and solvent-accessible surface area. For example, with the PME method, the dimer structure remains much closer to the initial crystal lographic structure with an average RMSD of 1.3 Angstrom +/- 0.1 Angstrom a nd 1.0 Angstrom +/- 0.1 Angstrom for all heavy and backbone atoms, respecti vely, in the last 200 ps; the respective values for the cutoff simulation a re 4.7 Angstrom +/- 0.3 Angstrom and 4.2 Angstrom +/- 0.3 Angstrom. The lar ge deviations observed in the cutoff simulation severely affected the stabi lity of the enzyme dimer and its complex with the bound product. This findi ng is contrary to that found in a similar study of the monomeric protein ub iquitin [Fox, T. & Kollman, P. A. Proteins Struct. Func. Genet. 25, 315-334 (1996)]. Unlike the earlier published work, the present study provides evi dence that the standard cutoff method is not generally valid for the study of protein complexes, or their subunits.