We have used a molecular modeling of both random and blocky sequence hydrogel networks of poly(N-vinyl-2-pyrrolidone-co-2-hydroxyethyl methacrylate) (P(VP-co-HEMA)) with a composition of VP:HEMA = 37:13 to investigate the effect of the monomeric sequence and the water content on the equilibrium structures and the mechanical and transport properties by full-atomistic molecular dynamics (MD) simulations. The degree of randomness of the monomer sequence for the random and the blocky copolymers, were 1.170 and 0.104, respectively, and the degree of polymerization was fixed at 50. The equilibrated density of the hydrogel was found to be larger for the random sequence than for the blocky sequence at low water contents (< 40 wt %), but this density difference decreased with increasing water content. The pair correlation function analysis shows that VP is more hydrophilic than HEMA and that the random sequence hydrogel is solvated more than the blocky sequence hydrogel at low water content, which disappears with increasing water content. Correspondingly, the water structure is more disrupted by the random sequence hydrogel at low water content but eventually develops the expected bulk-water-like structure with increasing water content. From mechanical deformation simulations, the stress-strain analysis showed that the VP is found to relax more efficiently, especially in the blocky sequence, so that the blocky sequence hydrogel shows less stress levels compared to the random sequence hydrogel. As the water content increases, the stress level becomes identical for both sequences. The elastic moduli of the hydrogels calculated from the constant strain energy minimization show the same trend with the stress-strain analysis. Ascorbic acid and D-glucose were used to study the effect of the monomeric sequence on the diffusion of small guest molecules within the hydrogels. By analyzing the pair correlation functions, it was found that the guest molecule has greater accessibility to the VP units than to the HEMA units with both monomeric sequences due to its higher hydrophilicity compared to the HEMA units. The monomeric sequence effect on the P(VP-co-HEMA) hydrogel is clearly observed with 20 wt % water content, but the monomeric sequence effect is significantly reduced with 40 wt % water content and disappears with 80 wt % water content. This is because the hydrophilic guest molecules are more likely to be associated with water molecules than with the polymer network at the high water content. By analyzing the mean square displacement, the displacement of the guest molecules and the inner surface area, it is also found that the guest molecule is confined in the system at 20 wt % water content, resulting in highly anomalous subdiffusion. Therefore, the diffusion of the guest molecules is directly affected by their interaction with the monomer units, the monomeric sequence and the geometrical confinement in the hydrogel at a low water content, but the monomeric sequence effect and the restriction on the diffusion of the guest molecule are significantly decreased with increasing the water content. We also investigated the de-swelling mechanisms of the surface-grafted poly(N-isopropylacrylamide) (P(NIPAAm)) brushes containing 1300 water molecules at 275 K, 290 K, 320 K, 345 K, and 370 K. We clearly observed the de-swelling of the water molecules for P(NIPAAm) above the lower critical solution temperature (LCST) (~305 K). Below the LCST, we did not observe the de-swelling of water molecules. Using the upper critical solution temperature (UCST) systems (poly(acrylamide) brushes) for comparison purposes, we did not observe the de-swelling of water molecules at a given range of temperatures. By analyzing the pair correlation functions and the coordination numbers, the de-swelling of the water molecules occurred distinctly around the isopropyl group of the P(NIPAAm) brush above the LCST because C(NIPAAm) does not offer sufficient interaction with the water molecules via the hydrogen bonding type of secondary interaction. We also found that the contribution of the N(NIPAAm)-O(water) pair is quite small because of the steric hindrance of the isopropyl group. By analyzing the change in the hydrogen bonds, the hydrogen bonds between polar groups and water molecules in the P(NIPAAm) brushes weaken with increasing temperature, which leads to the de-swelling of the water molecules out of the brushes above the LCST. Below the LCST, the change in the hydrogen bonds is not significant. Again, the contribution of the NH(NIPAAm)-water pairs is insignificant; the total number of hydrogen bonds is ~20, indicating that the interaction between the NH group and the water molecules is not significant due to steric hindrances. Lastly, we observed that the total surface area of the P(NIPAAm) brushes that is accessible to water molecules is decreased by collapsing the brushes followed by the de-swelling of water molecules above the LCST.