Structural discordance in HIV-1 Vpu from brain isolate alarms amyloid fibril forming behavior- a computational perspective.

ABSTRACT

HIV-1 being the most widespread type worldwide, its accounts for almost 95% of all infections including HIV associated dementia (HAD) that triggers neurological dysfunction and neurodegeneration in patients. The common features associated with HAD and other neurodegenerative diseases are accumulation of amyloid plaques, neuronal loss and deterioration of cognitive abilities, amongst which amyloid fibrillation is considered to be a hallmark. The success of effective therapeutics lies in the understanding of mechanisms leading to neurotoxicity. Few viral proteins like gp-120 are known to be involved in aggregation and enhancement of viral infectivity while comprehending the neurotoxic role of some other proteins is still underway. In the current study, amyloidogenic potential of HIV-1 Vpu protein from brain isolate is investigated through computational approaches. The aggregation propensity of brain derived HIV-1 Vpu was assessed by several amyloid prediction servers that projected the region 4-35 to be amyloidogenic. The protein structure was modeled and subjected to 70 ns molecular dynamics (MD) simulation to investigate the transformation of α-helical conformation of the predicted aggregate region into ß-sheet, proposing the protein's ability to initiate fibril formation that is central to amyloidogenic proteins. The structural features of brain derived HIV-1 Vpu were consistent with the in silico amyloid prediction results that depicts the conformational change in the region 8-28 of which residues Ala8, Ile9, Val10, Ala19, Ile20 and Val21 constitutes ß-sheet formation. The α-helix/ß-sheet discordance of the predicted region was reflected in the simulation study highlighting the possible structural transition associated with HIV-1 Vpu protein of brain isolate.