Cross Aggregation Activity of HIV‐1 Vpr Fragments With α‐Synuclein Aggregation‐Prone Regions Through the Computational Microscope

Abstract

HIV‐associated neurocognitive disorders (HAND) persist in a substantial fraction of people living with HIV, implicating ongoing viral protein mediated neurotoxicity. Viral protein R (Vpr) has emerged as a key contributor to neuronal dysfunction and impaired proteostasis, including dysregulation of the aggregation‐prone neuronal protein α‐synuclein (aSyn). However, the molecular basis by which Vpr influences aSyn aggregation, and whether this effect varies across HIV‐1 subtypes, remains poorly understood. Cross‐aggregation propensity between aggregation‐prone segments of human aSyn and HIV‐1 Vpr proteins was investigated using extensive all‐atom molecular dynamics simulations. Aggregation‐prone regions were first identified by sequence‐based prediction, followed by extensive simulations of mixed peptide systems under physiologically relevant conditions. Post‐simulation analyses, including normalized solvent‐accessible surface area, inter‐peptide contact mapping, secondary structure evolution, and normalized RMSF were used to quantify aggregation behavior and stability. This study demonstrates that the presence of certain Vpr peptides markedly accelerates aSyn aggregation, providing strong evidence for cross‐aggregation. The subtype‐dependent differences mirror reported variations in HIV neuropathogenicity. This study provides molecular‐level evidence that cross‐aggregation between Vpr fragments and aSyn aggregation prone segments represents a plausible mechanistic link between HIV infection and synucleinopathy‐like pathology, with important implications for HAND progression and subtype‐specific neurotoxicity.