క్లినికల్ & మెడికల్ బయోకెమిస్ట్రీ

నైరూప్య

Tetrasulfide Bridge (TTSB) Formation: An Extraordinary Intermediate Structure in the Architecture and Dynamics of HIV-1's gp120 Molecule

Harry F. Crevecoeur

Gp120, one of the molecules that execute HIV viral entry in CD4+ cells has a number of allosteric disulfide bridges. In this study we explore the dynamics of these potential disulfide (disulphide) bridges in the 3-D configuration (based on crystallography) and UNSW DBA analyses of various gp120 crystals. The data reveal the existence of a tetrasulfide (tetrasulphide) bridge (TTSB) which, together with a disulfide bridge, keeps two perpendicular beta sheets (namely V3 and V4) approximated in the architecture of the gp120 while allowing safe transfer of energy between the allosteric bonds. Analyses of multiple gp120 crystals reveal the existence of the TTSB to be more of an intermediate as opposed to a constant landmark, which implies more complex functions than just structural attributes. This TTSB, which is observed in various crystals of gp120, in various strains and clades of HIV-1, is demonstrated by various rendering software and some are also detected, reported and characterized by the UNSW Disulfide Bond Analysis (DBA) engine. This tetrasulfide bridge connects the allosteric bond Cys296-Cys331 to Cys385-Cys418, sometimes as CYS331:SG-CYS385:SG, and sometimes as CYS331:SG-CYS418:SG. Moreover in crystals 3TIH, 4LSR and 4R4N, we also observed an intermediate state of the TTSB where it presents a triangular formation in which the sulfur atom CYS331: SG binds to both CYS385:SG and CYS418:SG simultaneously, which represents an important intermediate in the functional dynamics of the gp120 molecule. The presence of this extraordinary structure (TTSB) does point to some intriguing insights in the multifunctional design and mechanics as well as some complex fragilities of the gp120 molecule, exposing a new target for antiviral therapy.