Static and dynamic water molecules in Cu,Zn superoxide dismutase

Abstract

Understanding protein hydration is a crucial, and often underestimated issue, in unraveling protein function. Molecular dynamics (MD) computer simulation can provide a microscopic description of the water behavior. We have applied such a simulative approach to dimeric Photobacterium leiognathi Cu,Zn superoxide dismutase, comparing the water molecule sites determined using 1.0 ns MD simulation with those detected by X-ray crystallography. Of the water molecules detected by the two techniques, 20% fall at common sites. These are evenly distributed over the protein surface and located around crevices, which represent the preferred hydration sites. The water mean residence time, estimated by means of a survival probability function on a given protein hydration shell, is relatively short and increases for low accessibility sites constituted by polar atoms. Water molecules trapped in the dimeric protein intersubunit cavity, as identified in the crystal structure, display a trajectory mainly confined within the cavity. The simulation shows that these water molecules are characterized by relatively short residence times, because they continuously change from one site to another within the cavity, thus hinting at the absence of any relationship between spatial and temporal order for solvent molecules in proximity of protein surface.

Polarizable molecular mechanics studies ofCu(I)/Zn(II)superoxide dismutase: Bimetallic binding site and structured waters

“…Cu/Zn‐SOD's have been the object of previous molecular dynamics (MD) simulations in the context of classical potentials . In line with these studies, and as a preliminary step toward docking of small molecules such as CN − , , photosensitizing agents, or inhibitors, in this study we investigate the structures, interaction energies, and electronic properties of structural waters in the vicinity of the Cu/Zn binding site of SOD.…”

“…It is to be underlined that much longer trajectories than those reported in Refs. and a fortiori in this work, might have to be considered to quantify the lifetimes, exchange rates of each individual water of the network, and their coexistence with a ligand diffusing toward the binding site. These should be enabled by the advent of a highly efficient and N‐scalable code to perform anisotropic polarizable MM and MD (APMM/APMD) simulations over the nanosecond limit [Piquemal et al, in preparation].…”

Prokaryotic Cu,Zn superoxide dismutases

“…The interface cavity is located at the centre of the subunit contact region and hosts buried water molecules, which establish additional hydrogen bonds between the facing residues, suggesting a contribution of the solvent in promoting subunit association. The importance of water in mediating subunit interactions was confirmed by a recent molecular dynamics study that identified the preferential hydration sites around the protein and within the cavity (Figure 3) [23]. A similar quaternary assembly is observed in A. pleuropeumoniae Cu,ZnSOD [12], while the subunit interface of S. typhimurium SOD displays a large number of residue substitutions which, despite maintaining a stable dimeric structure, modulate subunit recognition interactions in quaternary assembly [14].…”

Consideration of Water and Solvation Effects in Virtual Screening

“…The authors were able to detect a considerable overlap between the tightly bound water molecules identified on the basis of their MD simulation and crystallized water molecules. In contrast, Falconi et al [68] reported only a low overlap between hydration sites determined by MD simulation and X-ray crystallography. Reasons for the lack of agreement could be the different timescales observed by their 1 ns MD simulation and the X-ray experiment.…”