The human phosphoserine phosphatase (hPSP) catalyses the last step in the biosynthesis of L-serine. It involves conformational changes of the enzyme lid once the substrate, phosphoserine (PSer), is bound in the active site. Here, Elastic Network Model (ENM) is applied to the crystal structure of hPSP to probe the transition between open and closed conformations of hPSP. Molecular Dynamics (MD) simulations are carried out on several PSer-hPSP systems to characterise the intermolecular interactions and their effect on the dynamics of the enzyme lid. Systems involving either Ca++ or Mg++ are considered. The first ENM normal mode shows that an open-closed transition can be explained from a simple description of the enzyme in terms of harmonic potentials. Principal Component Analyses applied to the MD trajectories also highlight a trend for a closing/opening motion. Different PSer orientations inside the enzyme cavity are identified, i.e., either the carboxylate, the phosphate group of PSer, or both, are oriented towards the cation. The interaction patterns are analysed in terms of hydrogen bonds, electrostatics, and bond critical points of the electron density distributions. The latter approach yields a global description of the bonding intermolecular interactions. The PSer orientation determines the content of the cation coordination shell and the mobility of the substrate, while Lys158 and Thr182, involved in the reaction mechanism, are always in interaction with the substrate. Closed enzyme conformations involve Met52-Gln204, Arg49-Glu29, and Arg50-Glu29 interactions. Met52, as well as Arg49 and Arg50, also stabilize PSer inside the cavity.