Systematic Analysis of the HIV-1 Protease Active-Site Conformational Space Across 690 Crystal Structures

Hamlet Khachatryan — Tue, 16 Jun 2026 00:00:00 +0000

Human Immunodeficiency Virus-1 protease (HIV-1 PR) is among the most extensively studied drug targets in the Protein Data Bank (PDB), with more than 600 structural models predominantly derived by X-ray crystallography. This study presents a comprehensive analysis of the binding-site conformational space across the available structural record: 690 crystal structures deposited in the PDB with ≥90% sequence identity and resolution better than or equal to 2.50 Å, of which 684 were successfully featurized by pipeline. The structural dataset covers wild-type enzyme, crystallographic stabilization mutants, drug-resistant variants, and 452 distinct inhibitor binders. Each binding site was featurized as a volume-filling point cloud with six descriptors (electrostatic potential, lipophilicity, and pharmacophoric features) and represented as a geodesic distance matrix with further embedding in spectral distance space. Affinity propagation clustered all pockets into 16 discrete conformational states, with four dominant states accounting for 85% of all structures. The chemical space of the 452 extracted inhibitors is largely continuous, and its partitioning does not correspond to the receptor's conformational landscape; yet the molecular weight of binders correlates with cavity volume: heavier inhibitors disproportionately populate the largest closed-flap state, while lighter molecules favour a distinct, tighter binding envelope. This analysis provides a structural basis and insights for ensemble-based virtual screening, de novo generation of inhibitors, and the systematic interpretation of evidenced structure–ligand data across the HIV-1 PR inhibitor landscape.

Overvoltage Elimination of Dual-Branch Series–Parallel Charge Pumps with Thin Oxide Transistors

Vazgen Melikyan, Roman Ivanyan — Thu, 04 Jun 2026 00:00:00 +0000

Integrated circuits increasingly rely on on-chip generation of voltage levels beyond the nominal supply. Charge pumps provide this functionality using capacitors and switches, but their boosted internal nodes raise reliability concerns in scaled CMOS technologies, especially in processes offering only thin-oxide devices. Prior studies have shown that aging mechanisms such as bias temperature instability can noticeably alter the output voltage and startup behavior of conventional series-parallel charge pumps. This paper presents an aging-aware series–parallel voltage doubler that mitigates overstress at critical output nodes while preserving the intended voltage-boost operation. The circuit is sized to match the fresh-state characteristics of the reference design, enabling a fair comparison. Simulation results under long-term BTI stress confirm improved stability of the charge-pump behavior with reduced aging-induced drift.

Reports of NAS RA

Systematic Analysis of the HIV-1 Protease Active-Site Conformational Space Across 690 Crystal Structures

Overvoltage Elimination of Dual-Branch Series–Parallel Charge Pumps with Thin Oxide Transistors