biostudies-literatureKneller DWNIAID NIH HHSNational Institutes of HealthNational Science Foundation3586-3597https://www.ebi.ac.uk/biostudies/studies/S-EPMC8940534biostudies-literatureUnknown24(6)Biomacromolecules are inherently dynamic, and their dynamics are interwoven into function. The fast collective vibrational dynamics in proteins occurs in the low picosecond timescale corresponding to frequencies of ∼5-50 cm^-1. This sub-to-low THz frequency regime covers the low-amplitude collective breathing motions of a whole protein and vibrations of the constituent secondary structure elements, such as α-helices, β-sheets and loops. We have used inelastic neutron scattering experiments in combination with molecular dynamics simulations to demonstrate the vibrational dynamics softening of HIV-1 protease, a target of HIV/AIDS antivirals, upon binding of a tight clinical inhibitor darunavir. Changes in the vibrational density of states of matching structural elements in the two Physical chemistry chemical physics : PCCPJoint neutron/molecular dynamics vibrational spectroscopy reveals softening of HIV-1 protease upon binding of a tight inhibitor.PMC8940534grant ACI-1548562R01-AI148740R01 AI148740Gumbart JCKovalevsky ADaemen LLKneller DWPavlova AGerlits OCheng YfalseJoint neutron/molecular dynamics vibrational spectroscopy reveals softening of HIV-1 protease upon binding of a tight inhibitor.Biomacromolecules are inherently dynamic, and their dynamics are interwoven into function. The fast collective vibrational dynamics in proteins occurs in the low picosecond timescale corresponding to frequencies of ∼5-50 cm^-1. This sub-to-low THz frequency regime covers the low-amplitude collective breathing motions of a whole protein and vibrations of the constituent secondary structure elements, such as α-helices, β-sheets and loops. We have used inelastic neutron scattering experiments in combination with molecular dynamics simulations to demonstrate the vibrational dynamics softening of HIV-1 protease, a target of HIV/AIDS antivirals, upon binding of a tight clinical inhibitor darunavir. Changes in the vibrational density of states of matching structural elements in the two 2022-01-01T00:00:00Z2022 Feb2026-05-09T13:45:14.512Z2025-04-07T03:19:11.13ZS-EPMC89405343508999010.1039/d1cp05487b