Exploring the Reasons for Decrease in Binding Affinity of HIV-2 Against HIV-1 Protease Complex Using Interaction Entropy Under Polarized Force Field

Abstract

In this study, the differences of binding patterns between two type HIV (HIV-1 and HIV-2) protease and two inhibitors (darunavir and amprenavir) are analyzed and compared using the newly developed interaction entropy (IE) method for the entropy change calculation combined with the polarized force field. The functional role of protonation states in the two HIV-2 complexes is investigated and our study finds that the protonated OD1 atom of Asp25′ in B chain is the optimal choice. Those calculated binding free energies obtained from the polarized force field combined with IE method are significantly consistent with the experimental observed. The bridging water W301 is favorable to the binding of HIV-1 complexes; however, it is unfavorable to the HIV-2 complexes in current study. The volume of pocket, B-factor of Cα atoms and the distance of flap tip in HIV-2 complexes are smaller than that of HIV-1 consistently. These changes may cause localized rearrangement of residues lining their surface and finally result in the different binding mode for the two types HIV. Predicated hot-spot residues (Ala28/Ala28′, Ile50/Ile50′, and Ile84/Ile84′) are nearly same in the four systems. However, the contribution to the free energy of Asp30 residue is more favorable in HIV-1 system than in HIV-2 system. Current study, to some extent, reveals the origin for the decrease in binding affinity of inhibitors against HIV-2 compared with HIV-1 and will provides theoretical guidance for future design of potent dual inhibitors targeting two type HIV protease.

End-Point Binding Free Energy Calculation with MM/PBSA and MM/GBSA: Strategies and Applications in Drug Design

“…The interaction entropy method is a more recently developed entropy estimation method that considers only the fluctuations of the ligand–receptor interactions during the MD simulations and thus does not need additional computational cost . This method has been successfully used in many aspects of molecular interactions such as calculating hot spots for protein–protein interactions, ,− predicting absolute binding free energies for ligand–protein complexes, − etc. In one important work, Aldeghi et al systemically compared the accuracy of MM/PBSA and the alchemical method (TI) and found that incorporation of the interaction entropy into MM/PBSA can significantly improve its performance across all of the tested protocols, indicating that the interaction entropy method is a highly efficient method to improve the performance of the end-point binding free energy calculations.…”

Comparative study of the unbinding process of some HTLV-1 protease inhibitors using unbiased molecular dynamics simulations

“…In some research, protonation is not applied or not mentioned, or in some research, protonation state is applied in chain A. As we wanted a more complete outcome, we used protonation separately in both chains [ 26 , 27 ]. So after preparing complexes, each catalytic Asp was considered separately as an ionization state based on the monoprotonated (mp) form of the catalytic dyad Asp32-Asp32′ in the active site [ 28 ].…”

A fast–slow method to treat solute dynamics in explicit solvent

“…The fast–slow method explicit solvent model divides the entire system into two layers: a core layer and a peripheral layer. The core layer includes solute molecules (plus special solvent molecules that play a special role, such as bridging water 4,37 ) and the peripheral layer contains solvent molecules that act as the environment. The Hamiltonian of the entire system still uses the standard force field potential energy function:where ,, and represent the bond, angle, and dihedral energy, respectively.…”