Low-resolution X-ray crystallography and thermodynamic modeling studies have shown that allosteric HIV-1 integrase (IN) inhibitors which bind at the dimer interface of the IN catalytic core domain (CCD) promote aberrant IN multimerization by mediating intersubunit interactions between an external C-terminal domain (CTD) and the CCD-CCD dimer interface. However, the thermodynamic driving forces and kinetics of the ALLINI-induced aberrant IN multimerization remain largely unknown. Here we elucidate the molecular basis for the IN multimerization by simulating the formation of aberrant tetramers starting from IN dimers using microseconds explicit solvent molecular dynamics simulations. We found that the effective interactions of the oligomerization is short-ranged: the association kinetics is downhill when the CTDs and CCD-CCD dimer interfaces are separated by a critical distance of 8 Å or less, and with the two binding partners are aligned at the native orientation. Beyond this separation distance, the oligomerization kinetics is diffusion controlled. Intriguingly, this distance corresponds to the critical separation at which a dewetting transition occurs between two hydrophobic surfaces predicted by using simple macroscopic thermodynamics. To test whether the aberrant IN oligomerization is indeed driven by hydrophobic interactions, we have modified the solute-water van der Waals to make the solute more hydrophilic. When the solute-water Lennard-Jones well-depth is made deeper by ≥ 28 %, no oligomerization interface is formed even starting at less than the critical separation, suggesting that hydrophobic interaction could be one of the factors driving the downhill oligomerization. This finding appears to be consistent with the observation that several nonpolar to polar mutations at the mutimer interfacial region are found to abrogate multimerization.

Elucidating the free energy landscape and the thermodynamic basis of HIV-1 integrase multimerization induced by allosteric inhibitor

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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