Joint neutron/molecular dynamics vibrational spectroscopy reveals softening of HIV-1 protease upon binding of a tight inhibitor

Kneller, Daniel; Gerlits, Oksana; Daemen, Luke L.; Pavlova, Anna; Gumbart, James C.; Cheng, Yongqiang; Kovalevskyi, Andrii Y.

doi:10.1039/d1cp05487b

Title: Joint neutron/molecular dynamics vibrational spectroscopy reveals softening of HIV-1 protease upon binding of a tight inhibitor

Journal Article · 24 January 2022 · Physical Chemistry Chemical Physics. PCCP

DOI: https://doi.org/10.1039/d1cp05487b · OSTI ID:1844872

^[1]; Gerlits, Oksana ^[2]; Daemen, Luke L. ^[1]; Pavlova, Anna ^[3]; Gumbart, James C. ^[3];

^[1];

^[1]

Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Tennessee Wesleyan Univ., Athens, TN (United States)
Georgia Institute of Technology, Atlanta, GA (United States)

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 monomers of the homodimeric protein are not identical, indicating asymmetric effect of darunavir on the vibrational dynamics. Three of the 11 major secondary structure elements contribute over 40% to the overall changes in the vibrational density of states upon darunavir binding. Molecular dynamics simulations informed by experiments allowed us to estimate that the altered vibrational dynamics of the protease would contribute -3.6 kcal/mol^-1 at 300 K, or 25%, to the free energy of darunavir binding. As HIV-1 protease drug resistance remains a concern, our results open a new avenue to help establish a direct quantitative link between protein vibrational dynamics and drug resistance.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH); National Science Foundation (NSF)

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1844872

Journal Information:: Physical Chemistry Chemical Physics. PCCP, Journal Name: Physical Chemistry Chemical Physics. PCCP Journal Issue: 6 Vol. 24; ISSN 1463-9076

Publisher:: Royal Society of ChemistryCopyright Statement

Country of Publication:: United States

Language:: English

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