The role of salt concentration and magnesium binding in HIV-1 subtype-A and subtype-B kissing loop monomer structures

Abstract

The subtype-B monomers of the human immunodeficiency virus type-1 (HIV-1) have experimentally been shown to dimerize at high salt concentration or in the presence of magnesium, while the dimerization of the subtype-A monomers requires magnesium binding at the G₂₇₃ or G₂₇₄ phosphate groups regardless of salt concentration. We used explicit solvent molecular dynamics (MD) simulations to investigate the conformational changes in subtype-A and -B monomers in different salt concentrations, and we found that our MD simulation results are consistent with those of experiments. At low salt concentration, hairpin loop structures of both subtypes were deformed and bases in the hairpin loop were turned inside. At high salt concentrations, the subtype-B monomer maintained the hairpin loop shape and most bases in the hairpin loop pointed out, while the subtype-A monomer showed a severe deformation. We also found that the flanking bases in the subtype-B stabilize the hairpin loop, while the flanking base G₂₇₃ in the subtype-A caused a significant deformation. However, a bound magnesium ion at the G₂₇₃ or G₂₇₄ phosphate groups controlled the behavior of the G₂₇₃ base and prevented the subtype-A monomer from deformation. We also applied restraints to both subtypes to examine the role of high salt concentration or magnesium binding. While restraints were applied, both subtypes at 0 M salt concentration maintained their shapes. However, when restraints were removed, they deformed significantly. Therefore, we suggest that the dimerization of both subtypes requires the proper conformation of the monomers which is induced by the appropriate salt strength and magnesium ion binding.

Keywords:

• HIV-1 dimerization
• HIV-1 subtype-A dimerization
• HIV-1 subtype-B dimerization
• Ion concentration
• Magnesium binding
• RNA molecular dynamics simulations

Acknowledgments

We wish to thank the National Cancer Institute′s Advanced Biomedical Computing Center (ABCC) of the Frederick National Laboratory for Cancer Research for the computational support. We also thank the NIH Fellows Editorial Board for editorial assistance on a late version of the manuscript. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.