A key factor for improving the sensitivity and performance of immunosensors based on mechanical–plasmonic methods is the orientation of the antibody proteins immobilized on the inorganic surface. Although experimental techniques fail to determine surface phenomena at the molecular level, modern simulations open the possibility for improving our understanding of protein–surface interactions. In this work, replica exchange molecular dynamics (REMD) simulations have been used to model the IgG1 protein tethered onto the amorphous silica surface by considering a united-atom model and a relatively large system (2500 nm2 surface). Additional molecular dynamics (MD) simulations have been conducted to derive an atomistic model for the amorphous silica surface using the cristobalite crystal structure as a starting point and to examine the structure of the free IgG1 antibody in the solution for comparison when immobilized. Analyses of the trajectories obtained for the tethered IgG1, which was sampled considering 32 different temperatures, have been used to define the geometry of the protein with respect to the inorganic surface. The tilt angle of the protein with respect to the surface plane increases with temperature, the most populated values being 24, 66, and 87° at the lowest (250 K), room (298 K), and the highest (380 K) temperatures. This variation indicates that the importance of protein–surface interactions decreases with increasing temperature. The influence of the surface on the structure of the antibody is very significant in the constant region, which is directly involved in the tethering process, while it is relatively unimportant for the antigen-binding fragments, which are farthest from the surface. These results are expected to contribute to the development of improved mechanical–plasmonic sensor microarrays in the near future.