To investigate how fruity substances influence a roasted aroma, the threshold values of 17 common edible fruity substances were determined using the threshold method. Based on the threshold values, these fruity substances were mixed with 2,3,5-trimethylpyrazine at different mass concentrations, and their interaction with roasted pyrazines in the mixtures then examined using the S-curve method. This study found that 13 of the fruity substances tested had synergistic effects with pyrazines, two substances (ethyl methylphenylglycidate and amyl caproate) exhibited enhancing effects, and another two substances (nootkatone and limonene) displayed masking effects on pyrazines. Based on the sensory results, a 200-ns molecular dynamics simulation was carried out for ethyl acetate and nootkatone, which demonstrated synergistic and masking effects, respectively, to further verify ligand–receptor interactions. The influence that the addition of fruity substances and pyrazines has on protein system stability can be objectively expressed by the root-mean-square deviation (RMSD) and number of hydrogen and hydrophobic bonds, which were used to study interactions between the two compounds. The results obtained through the RMSD and number of hydrogen and hydrophobic bonds were consistent with those obtained through the S-curve method. These findings demonstrate that molecular dynamics simulations can further verify sensory results, thereby providing a theoretical basis for the study of compound interactions and theoretical guidance for future food production and flavoring.