LAUSR

The gp120 surface subunit of HIV-1 envelope lycoprotein (Env) is the key component for the viral entry process through interaction with the CD4 binding site (CD4bs) of the primary receptor CD4. The point mutant was introduced into SD1, a CD4 D1 variant, to enhance the interaction with HIV-1 gp120.The three-dimensional structures of gp120 and SD1 were determined using homology modeling based on the results previously determined by X-ray crystallography. The binding models were carried out via protein–protein docking tools. The 5 best docking solutions were retained according to the docking scores and were used for structural assessment. Our results demonstrated the consistency between the 3D models of gp120 and SD1 predicted by molecular docking calculations and the co-crystallized data available. We first discovered that most residues in SD1 that interacted with gp120 were located within the region 6–94 of the first N-terminal D1 domain of CD4. SD1 bound to gp120 stably at which 15 residues formed 20 hydrogen bonds with 16 residues of gp120. Five pairs of electrostatic interactions between positively and negatively charged side chains of amino acids were identified in the SD1-gp120 interface, which showed an increased number of electrostatic interactions with gp120. The mutant in the D1 domain of human CD4 receptor could strengthen binding affinity with HIV-1 gp120 and might improve the interaction pattern of the neighboring residues. The sequence analysis of gp120 suggested that Asp186, Asn189, Arg191, Glu293, Phe318 and Tyr319 were located in the variable regions of gp120, which may be HIV-1 AE strain-specific amino acid residues. Together, the results presented in this study contributed to a better understanding of the changes in the interaction between the gp120 protein and the human host CD4 receptor associated with point mutation in the D1 domain. The stabilized derivative of human CD4 D1 should serve as a promising target for therapeutics development in HIV-1 vaccine and viral entry inhibitor and may warrant further investigation.