The Low-Barrier Double-Well Potential in Bound HIV Protease Systems and Small Analogs

The presence of a low-barrier hydrogen bond (LBHB) in HIV Protease and other aspartyl proteases as well as its implications in drug design has been the subject of intense study. In this research project, we utilize a Numerov procedure to characterize the Od1-H-Od1 hydrogen bond (HB) in HIV protease systems where the enzyme is bound to highly symmetric inhibitors. We also investigate small compounds that present an LBHB and serve as analogs. Our methodology fully traces the shape of the HB’s potential energy curve. The potential is used to obtain numerical solutions to the wave functions and vibrational energies of hydrogen, deuterium, and tritium. The vibrational eigenfunctions are used to compute expectation values for interatomic distances and vibrationally and thermally averaged spectroscopic properties of the O-H-O HB. Our predictions of isotope effects on the chemical shift of small analogs are consistent with experimental measurements. The results support the predictive power of this method and its potential use in screening inhibitors of aspartyl proteases