Large multidomain proteins occur in different conformational states to function. Detection and monitoring of these different structural states are of crucial interest for understanding the mechanics of proteins. Using computational methods, we show that different protein conformational states of the two-domain 70 kDa human Heat-shock protein (hHsp70), with similar vibrational density of states, lead to remarkably different far-IR spectra at acoustical frequencies (ν < 300 GHz). We found that the slow damped motions of the positively charged residues of hHsp70 contribute the most to collective IR active modes at low frequencies (ν < 300 GHz). We predicted that different structural states and functional modes of large proteins, such as hHsp70, might be detected in the sub-THz frequency range by single-molecule spectroscopy similar to the recent extraordinary acoustic Raman spectroscopy (Wheaton S.; Nat. Photonics2015, 9, 68-72).